Prodrugs of phenolic TRPV1 agonists

ABSTRACT

Described herein are compounds, pharmaceutical compositions and medicaments that include such compounds, and methods of using such compounds to modulate transient receptor potential vanilloid 1 receptor (TRPV1) activity.

CROSS-REFERENCE

This application is a continuation of U.S. application Ser. No.15/529,076, filed on May 23, 2017, which was National Phase ofPCT/US2015/062531, filed on Nov. 24, 2015, which was a continuationinpart of U.S. patent application Ser. No. 14/743,375, filed on Jun. 18,2015, which claims benefit of U.S. Provisional Application No.62/084,515, filed on Nov. 25, 2014, all of which are herein incorporatedby reference in their entirety.

BACKGROUND OF THE INVENTION

Described herein are compounds, pharmaceutical compositions andmedicaments that include such compounds, and methods of using suchcompounds to modulate the transient receptor potential vanilloid 1receptor (TRPV1) activity.

SUMMARY OF THE INVENTION

In one aspect, described herein is a compound having the structure ofFormula (I):

wherein:

Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolichydroxyl group is replaced by a covalent bond to—C(O)—X—(C(R₁)(R₂))_(n)—Z;

X is —C(R₁)(R₂)—, —O—, —N(R₅)— or —S—;

n is an integer from 1 to 10;

Z is —NR₃R₄ or —CO₂H;

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group, or R₁ and R₅groups on adjacent atoms, together with the atoms to which they areattached, form a substituted or unsubstituted heterocycloalkyl group;and

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl;

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof.

In one embodiment is a compound of Formula (I), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is substituted or unsubstituted alkyl. Inanother embodiment is a compound of Formula (I), wherein Y is

is independently selected from hydrogen, halogen, —CN, —NH₂, —NH(CH₃),—N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl or alkylsubstituted with one or more groups selected from halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In anotherembodiment is a compound of Formula (I), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkylor alkyl substituted with one or more groups selected from halogen, —CN,—NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In another embodiment is a compound of Formula (I), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl.

In some embodiments is a compound of Formula (I), wherein Y is

In some embodiments is a compound of Formula (I), wherein Z is —NR₃R₄.In some embodiments is a compound of Formula (I), wherein Z is —NR₃R₄;R₃ is hydrogen; and R₄ is H or substituted or unsubstituted alkyl. Insome embodiments is a compound of Formula (I), wherein X is —N(R₅)—. Insome embodiments is a compound of Formula (I), wherein X is —N(R₅)—, andR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup. In some embodiments is a compound of Formula (I), wherein X is—N(R₅)—, and R₁ and R₅ groups on adjacent atoms, together with the atomsto which they are attached, form a substituted or unsubstitutedheterocycloalkyl group wherein the heterocycloalkyl group is asubstituted or unsubstituted pyrrolidine ring, substituted orunsubstituted piperidine ring, or substituted or unsubstitutedpiperazine ring. In some embodiments is a compound of Formula (I),wherein Y is

In some embodiments is a compound of Formula (I), having the structure

In some embodiments is a compound of Formula (I), wherein Y is

In some embodiments is a compound of Formula (I), wherein Z is —NR₃R₄.In some embodiments is a compound of Formula (I), wherein Z is —NR₃R₄;R₃ is hydrogen; and R₄ is H or substituted or unsubstituted alkyl. Insome embodiments is a compound of Formula (I), wherein X is —N(R₅)—. Insome embodiments is a compound of Formula (I), wherein X is —N(R₅)— andR₅ is substituted or unsubstituted alkyl. In some embodiments is acompound of Formula (I), wherein X is —N(R₅)— and R₅ is unsubstitutedalkyl. In some embodiments is a compound of Formula (I), wherein X is—N(R₅)— and R₅ is —CH₃. In some embodiments is a compound of Formula(I), wherein X is —N(R₅)— and R₅ is substituted alkyl. In someembodiments is a compound of Formula (I), wherein X is —N(R₅)— and R₅ is—CH₂CH₂NH₂. In some embodiments is a compound of Formula (I), wherein Xis —N(R₅)— and R₅ is —CH₂CH₂NH(alkyl). In some embodiments is a compoundof Formula (I), wherein X is —O—. In some embodiments is a compound ofFormula (I), wherein X is —C(R₁)(R₂)—. In some embodiments is a compoundof Formula (I), wherein n is an integer from 2 to 6. In some embodimentsis a compound of Formula (I), wherein n is 2. In some embodiments is acompound of Formula (I), wherein n is 3. In some embodiments is acompound of Formula (I), wherein n is 4.

In some embodiments is a compound of Formula (I) having the structure ofFormula (II):

wherein Z is —NR₃R₄, and n is an integer from 2 to 10. In someembodiments is a compound of Formula (II), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is substituted or unsubstituted alkyl. Insome embodiments is a compound of Formula (II), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl or alkylsubstituted with one or more groups selected from halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In someembodiments is a compound of Formula (II), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkylor alkyl substituted with one or more groups selected from halogen, —CN,—NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some embodiments is a compound of Formula (II), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl.In some embodiments is a compound of Formula (II), wherein Y is

In some embodiments is a compound of Formula (II), having the structureof Formula (IIa):

wherein p is an integer from 1 to 9. In some embodiments is a compoundof Formula (IIa), having the structure of Formula (IIaa):

In some embodiments is a compound of Formula (II), (IIa), or (IIaa),wherein R₁ and R₅ groups on adjacent atoms, together with the atoms towhich they are attached, form a substituted or unsubstitutedheterocycloalkyl group. In some embodiments is a compound of Formula(II), (IIa), or (IIaa), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group and the heterocycloalkyl groupis a substituted or unsubstituted pyrrolidine ring, substituted orunsubstituted piperidine ring, or substituted or unsubstitutedpiperazine ring. In some embodiments is a compound of Formula (II),(IIa), or (IIaa), wherein R₁ and R₅ groups on adjacent atoms, togetherwith the atoms to which they are attached, form a substituted orunsubstituted heterocycloalkyl group; the heterocycloalkyl group is asubstituted or unsubstituted pyrrolidine ring, substituted orunsubstituted piperidine ring, or substituted or unsubstitutedpiperazine ring; R₃ is hydrogen; and R₄ is hydrogen or methyl. In someembodiments is a compound of Formula (II), (IIa), or (IIaa), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup; the heterocycloalkyl group is a substituted or unsubstitutedpyrrolidine ring, substituted or unsubstituted piperidine ring, orsubstituted or unsubstituted piperazine ring; R₃ is hydrogen; and R₄ ishydrogen. In some embodiments is a compound of Formula (II), (IIa), or(IIaa), wherein R₁ and R₅ groups on adjacent atoms, together with theatoms to which they are attached, form a substituted or unsubstitutedheterocycloalkyl group; the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring, substituted or unsubstituted piperidinering, or substituted or unsubstituted piperazine ring; R₃ is hydrogen;and R₄ is methyl. In some embodiments is a compound of Formula (II),(IIa), or (IIaa), having the structure:

wherein R₄ is hydrogen or methyl; and p is an integer from 1 to 9.In some embodiments is a compound of Formula (II), (IIa), or (IIaa),having the structure:

wherein R₄ is hydrogen or methyl; and p is an integer from 1 to 9.In some embodiments is a compound of Formula (II), having the structureof Formula (IIb):

wherein p is an integer from 1 to 9. In some embodiments is a compoundof Formula (IIb), having the structure of Formula (IIbb):

In some embodiments is a compound of Formula (IIb) or (IIbb), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup. In some embodiments is a compound of Formula (IIb) or (IIbb),wherein R₁ and R₅ groups on adjacent atoms, together with the atoms towhich they are attached, form a substituted or unsubstitutedheterocycloalkyl group, and the heterocycloalkyl group is a substitutedor unsubstituted pyrrolidine ring, substituted or unsubstitutedpiperidine ring, or substituted or unsubstituted piperazine ring. Insome embodiments is a compound of Formula (IIb) or (IIbb), wherein R₃ ishydrogen and R₄ is hydrogen or methyl. In some embodiments is a compoundof Formula (IIb) or (IIbb), wherein R₃ is hydrogen and R₄ is hydrogen.

In some embodiments is a compound of Formula (IIa), (IIaa), (IIb), or(IIbb), wherein p is 1. In some embodiments is a compound of Formula(IIa), (IIaa), (IIb), or (IIbb), wherein p is 2.

In some embodiments is a compound of Formula (I) having the structure ofFormula (III):

In some embodiments is a compound of Formula (III), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is substituted or unsubstituted alkyl. Insome embodiments is a compound of Formula (III), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl or alkylsubstituted with one or more groups selected from halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In someembodiments is a compound of Formula (III), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkylor alkyl substituted with one or more groups selected from halogen, —CN,—NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some embodiments is a compound of Formula (III), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl.In some embodiments is a compound of Formula (III), wherein Y is

In some embodiments is a compound of Formula (III), having the structureof Formula (IIIa):

wherein p is an integer from 0 to 9. In some embodiments is a compoundof Formula (IIIa), having the structure of Formula (IIIaa):

In some embodiments is a compound of Formula (III), having the structureof Formula (IIIb):

wherein p is an integer from 0 to 9. In some embodiments is a compoundof Formula (IIIb), having the structure of Formula (IIIbb):

For any and all embodiments described herein, substituents are selectedfrom among a subset of listed alternatives.

In some embodiments is a compound of Formula (III), (IIIa), (IIIaa),(IIIb), or (IIIbb), wherein each R₁ and each R₂ are hydrogen. In someembodiments is a compound of Formula (III), (IIIa), (IIIaa), (IIIb), or(IIIbb), wherein at least one R₁ is substituted or unsubstituted alkyl.In some embodiments is a compound of Formula (IIIa), (IIIaa), (IIIb), or(IIIbb), wherein p is 0. In some embodiments is a compound of Formula(IIIa), (IIIaa), (IIIb), or (IIIbb), wherein p is 1. In some embodimentsis a compound of Formula (IIIa), (IIIaa), (IIIb), or (IIIbb), wherein pis 2.

In another aspect is a pharmaceutical composition comprising a compoundof Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc),(IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa),(IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee),(IIIf), (IIIff), (IV), (V), or (VI), or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate, or hydrate thereof, and apharmaceutically acceptable diluent, excipient or binder. In someembodiments, the pharmaceutical composition is formulated forintravenous injection, subcutaneous injection, intramuscular injection,intraperitoneal injection, perineural injection, neuraxial injection,intra-articular injection, oral administration, or topicaladministration.

In another aspect is a method of treating pain in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or hydratethereof. In some embodiments is a method of treating pain in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb),(IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III),(IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd),(IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof, wherein the pain is associated with post-operativepain, chronic post-surgical pain, neuropathic pain, postherpeticneuralgia, diabetic neuropathy, HIV-associated neuropathy, complexregional pain syndrome, cancer, nerve injury, cancer chemotherapy,vulvodynia, trauma, surgery, chronic musculoskeletal pain, lower backpain, osteoarthritis or rheumatoid arthritis. In some embodiments is amethod of treating pain in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of Formula (I),(II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof, wherein the compound isadministered locally, dermally, transdermally or systemically.

DETAILED DESCRIPTION

Capsaicin, the main ingredient responsible for the hot pungent taste ofchili peppers, is an alkaloid found in the Capsicum family. Capsaicin(8-methyl-N-vanillyl-6-nonenamide) is a highly selective agonist fortransient receptor potential vanilloid 1 receptor (TRPV1; formerly knownas vanilloid receptor 1 (VR1)), a ligand-gated, non-selective cationchannel. TRPV1 is preferentially expressed on small-diameter sensoryneurons, especially those A- and C-fibers which specialize in thedetection of painful or noxious sensations. TRPV1 responds to noxiousstimuli including capsaicin, heat, and extracellular acidification, andwill integrate simultaneous exposures to these stimuli. (Caterina M J,Julius D. The vanilloid receptor: a molecular gateway to the painpathway. Annu Rev Neurosci. 2001. 24:487-517).

TRPV1 agonists, such as capsaicin, have been shown to diminish pain invarious settings, but there are problems associated with their use. Theinitial effects of TRPV1-expressing (capsaicin-sensitive) nociceptorsactivation are burning sensations, hyperalgesia, allodynia, anderythema. However, after prolonged exposure to low-concentrationcapsaicin or single exposures to high-concentration capsaicin or otherTRPV1 agonists, the small-diameter sensory axons become less sensitiveto a variety of stimuli, including capsaicin or thermal stimuli. Thisprolonged exposure is also characterized by reduced pain responses.These later-stage effects of capsaicin are frequently referred to as“desensitization” and are the rationale for the development of capsaicinformulations for the treatment of various pain syndromes and otherconditions. (Bley, K. R. Recent developments in transient receptorpotential vanilloid receptor 1 agonist-based therapies. Expert OpinInvestig Drugs. 2004. 13(11): 1445-1456).

In addition, capsaicin and other TRPV1 agonists have very limited watersolubility, are extremely potent irritants requiring special equipmentwhen handling and, due to their limited water solubility, are notreadily mixed with common drugs that are procured as aqueous solutions.Therefore, the use of non-aqueous formulations is necessary to deliversubstantial quantities of capsaicin or other TRPV1 agonists. Theseformulations are frequently not aligned with currentpractices/procedures, especially with respect to sterile aqueoussolutions used in surgery. Additionally, due to the potent ability ofcapsaicin to cause irritation, it would be preferable to utilize awater-soluble prodrug of capsaicin that minimizes capsaicin's activityuntil the prodrug reaches the desired site of activity.

Therefore, it would be desirable to provide TRPV1 agonist prodrugswith: 1) increased water solubility, 2) the potential for reduced ordelayed pungency associated with the administration of TRPV1 agonistsand 3) have the ability to be delivered in a rapid manner (half-life ofdelivery of TRPV1 agonist in less than 30 min) or in a delayed manner(half-life of delivery of TRPV1 agonist in greater than 30 min). Inaddition, it may be desirable to utilize chemical formulations/additivesto delay the initiation of prodrug conversion. Furthermore, it would bedesirable to provide TRPV1 agonist prodrugs that are soluble in aqueoussterile injectable formulations to the intended site of action. Finally,in some cases it would be desirable to deliver another pharmacologicallyactive compound(s) along with a capsaicin prodrug or other TRPV1 agonistprodrug, especially a local anesthetic agent.

Accordingly, the compounds described herein are directed to novelwater-soluble prodrugs of TRPV1 agonists and their methods of synthesisand use. These prodrug TRPV1 agonist derivatives revert to the activeparent compound when exposed to physiological conditions. The compoundshave significantly higher hydrophilicity/water solubility than theirparent drugs and, hence, are better able to be incorporated intocommonly used aqueous formulations. Further described herein is a methodof increasing the water solubility of capsaicin, its analogs and otherTRPV1 agonists, by modifying the parent molecule's chemical structurewith hydrophilic moieties. In some embodiments described herein, theintroduction of basic moieties capable of being protonated under acidicconditions increases the solubility of the TRPV1 prodrug. In someembodiments described herein, the introduction of acidic moietiescapable of increasing the overall hydrophilic character increases thesolubility of the TRPV1 prodrug. The prodrugs described herein aredesigned such that the parent drug is released, via cyclization-releasereactions, under well-defined rates after the prodrug has been deliveredto the body and/or is exposed to specific physiological conditions. Thechemical-release kinetics of the parent drug may impart two importantproperties: (a) potentially reduced and/or delayed pungency due to theavoidance of the rapid delivery of a bolus dose of the TRPV1 agonist and(b) rapid or delayed release of the parent TRPV1 agonist from theprodrug for tuning of specific pharmacological activity/results. Suchstructural modifications eliminate the reliance on special requirementsfor formulations or delivery devices in order to 1) accommodate the verylow water solubility of many TRPV1 agonists/capsaicinoids and 2) reducethe acute pungency associated with the administration of TRPV1 agonists.Additionally, water-soluble prodrugs are desired when co-deliveringother medications, especially when administering multiple sterile agentsvia injection.

The capsaicin, capsaicinoids or other TRPV1 agonist prodrugs describedherein are chemically modified to control the rate at which thecapsaicin, capsaicinoid, or other TRPV1 agonist is bioavailable throughpH controlled, intramolecular cyclization-release reactions. In someembodiments, the TRPV1 agonist prodrugs described herein have prolongedstability at pH levels suitable for making pharmaceutical formulations,but break down in vivo under physiological condition in a controlledmanner. After parenteral administration, the compounds of Formula (I),(II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI) are converted to the parent drug (TRPV1 agonist) via the pHcontrolled, cyclization-release reaction. The rate at which the prodrugconverts is dictated by the cyclization-release reaction, which can bemodified by the addition of buffers. In some embodiments, the bufferprovides a time window where turnover to parent drug is significantlydelayed until the return of physiological conditions. In someembodiments, the release of parent drug is tuned to provide for rapidrelease based on the rate of the intramolecular cyclization release. Insome embodiments, the release of parent drug is tuned to provide fordelayed release based on the rate of the intramolecular cyclizationrelease. In some embodiments described herein, the parent drug isreleased by an amine-based intramolecular cyclization (D=TRPV1 agonist):

In some embodiments described herein, the parent drug is released by acarboxylate-based intramolecular cyclization (D=TRPV1 agonist):

In some embodiments, the cyclization rate (t_(1/2)) at 37° C., pH 7.4,is between 10 seconds and 10 hours. In some embodiments, the cyclizationrate (t_(1/2)) at 37° C., pH 7.4, is between 10 seconds and 1 hour. Insome embodiments, the cyclization rate (t_(1/2)) at 37° C., pH 7.4, isbetween 10 seconds and 30 minutes. In some embodiments, the cyclizationrate (t_(1/2)) at 37° C., pH 7.4, is between 1 minute and 10 hours. Insome embodiments, the cyclization rate (t_(1/2)) at 37° C., pH 7.4, isbetween 1 minute and 30 minutes. In some embodiments, the cyclizationrate (t_(1/2)) at 37° C., pH 7.4, is between 2 minutes and 30 minutes.In some embodiments, the cyclization rate (t_(1/2)) at 37° C., pH 7.4,is between 5 minutes and 30 minutes. In some embodiments, thecyclization rate (t_(1/2)) at 37° C., pH 7.4, is between 2 minutes and15 minutes. In some embodiments, the cyclization rate (t_(1/2)) at 37°C., pH 7.4, is between 5 minutes and 15 minutes. In some embodiments,the cyclization rate (t_(1/2)) at 37° C., pH 7.4, is between 15 minutesand 2 hours. In some embodiments, the cyclization rate (t_(1/2)) at 37°C., pH 7.4, is between 15 minutes and 1.5 hours. In some embodiments,the cyclization rate (t_(1/2)) at 37° C., pH 7.4, is between 15 minutesand 1 hour. In some embodiments, the cyclization rate (t_(1/2)) at 37°C., pH 7.4, is between 30 minutes and 2 hours. In some embodiments, thecyclization rate (t_(1/2)) at 37° C., pH 7.4, is between 30 minutes and1.5 hours. In some embodiments, the cyclization rate (t_(1/2)) at 37°C., pH 7.4, is between 30 minutes and 1 hour. In some embodiments, thecyclization rate (t_(1/2)) at 37° C., pH 7.4, is between 1 hour and 4hours. In some embodiments, the cyclization rate (t_(1/2)) at 37° C., pH7.4, is between 1 hour and 3 hours. In some embodiments, the cyclizationrate (t_(1/2)) at 37° C., pH 7.4, is between 1 hour and 2 hours. In someembodiments, the cyclization rate (t_(1/2)) at 37° C., pH 7.4, isbetween 2 hours and 10 hours. In some embodiments, the cyclization rate(t_(1/2)) at 37° C., pH 7.4, is between 2 hours and 6 hours. In someembodiments, the cyclization rate (t_(1/2)) at 37° C., pH 7.4, isbetween 2 hours and 4 hours. In some embodiments, the cyclization rate(t_(1/2)) at 37° C., pH 7.4, is between 2 hours and 3 hours. In someembodiments, the cyclization rate (t_(1/2)) at 37° C., pH 7.4, isbetween 3 hours and 5 hours. In some embodiments, the cyclization rate(t_(1/2)) at 37° C., pH 7.4, is between 4 hours and 6 hours. In someembodiments, the cyclization rate (t_(1/2)) at 37° C., pH 7.4, isbetween 5 hours and 7 hours. In some embodiments, the cyclization rate(t_(1/2)) at 37° C., pH 7.4, is between 6 hours and 8 hours. In someembodiments, the cyclization rate (t_(1/2)) at 37° C., pH 7.4, isbetween 7 hours and 9 hours. In some embodiments, the cyclization rate(t_(1/2)) at 37° C., pH 7.4, is between 8 hours and 10 hours.

Compounds

In one aspect, described herein is a compound having the structure ofFormula (I):

wherein:

Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolichydroxyl group is replaced by a covalent bond to—C(O)—X—(C(R₁)(R₂))_(n)—Z;

X is —C(R₁)(R₂)—, —O—, —N(R₅)— or —S—;

n is an integer from 1 to 10;

Z is —NR₃R₄ or —CO₂H;

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group, or R₁ and R₅groups on adjacent atoms, together with the atoms to which they areattached, form a substituted or unsubstituted heterocycloalkyl group;and

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

For any and all of the embodiments, substituents are selected from amongfrom a subset of the listed alternatives. For example, in someembodiments is a compound of Formula (I), wherein Z is —NR₃R₄. In otherembodiments is a compound of Formula (I), wherein Z is —CO₂H.

In some embodiments is a compound of Formula (I), wherein Y is J R₆ isindependently selected from hydrogen, halogen, —CN, —NH₂, —NH(CH₃),—N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is substituted or unsubstituted alkyl. Insome embodiments is a compound of Formula (I), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl or alkylsubstituted with one or more groups selected from halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In someembodiments is a compound of Formula (I), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkylor alkyl substituted with one or more groups selected from halogen, —CN,—NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some embodiments is a compound of Formula (I), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl.

In some embodiments is a compound of Formula (I), wherein Y is

In some embodiments is a compound of Formula (I), wherein Y is

In some embodiments is a compound of Formula (I), wherein Y is

In some embodiments is a compound of Formula (I), wherein Y is

In some embodiments is a compound of Formula (I), wherein Y is

In some embodiments is a compound of Formula (I), wherein Y is

In some embodiments is a compound of Formula (I), wherein X is —O—. Insome embodiments is a compound of Formula (I), wherein X is —S—. In someembodiments is a compound of Formula (I), wherein X is —C(R₁)(R₂)—. Insome embodiments is a compound of Formula (I), wherein X is —C(R₁)(R₂)—and R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, or substituted or unsubstituted aryl. In someembodiments is a compound of Formula (I), wherein X is —CH₂—. In someembodiments is a compound of Formula (I), wherein X is —CH(CH₃)—. Insome embodiments is a compound of Formula (I), wherein X is —C(CH₃)₂—.In some embodiments is a compound of Formula (I), wherein X is—C(R₁)(R₂)— and two R₁ or R₂ groups on adjacent carbon atoms, togetherwith the carbon atoms to which they are attached, form a substituted orunsubstituted cycloalkyl group. In some embodiments is a compound ofFormula (I), wherein X is —N(R₅)—. In some embodiments is a compound ofFormula (I), wherein X is —N(R₅)— and R₅ is substituted or unsubstitutedalkyl. In some embodiments is a compound of Formula (I), wherein X is—N(R₅)— and R₅ is unsubstituted alkyl. In some embodiments is a compoundof Formula (I), wherein X is —N(R₅)— and R₅ is substituted alkyl. Insome embodiments is a compound of Formula (I), wherein X is —N(R₅)— andR₅ is substituted or unsubstituted aryl. In some embodiments is acompound of Formula (I), wherein X is —N(R₅)— and R₅ is substitutedphenyl. In some embodiments is a compound of Formula (I), wherein X is—N(R₅)— and R₅ is unsubstituted phenyl. In some embodiments is acompound of Formula (I), wherein X is —NH—. In some embodiments is acompound of Formula (I), wherein X is —N(CH₃)—. In some embodiments is acompound of Formula (I), wherein X is —N(CH₂CH₃)—. In some embodimentsis a compound of Formula (I), wherein X is —N(CH₂CH₂NH₂)—. In someembodiments is a compound of Formula (I), wherein X is—N(CH₂CH₂NH(alkyl)-. In some embodiments is a compound of Formula (I),wherein X is —N(CH₂CH₂NH(CH₃))—. In a further embodiment of any of theaforementioned embodiments is a compound of Formula (I), wherein Z is—CO₂H. In another embodiment of any of the aforementioned embodiments isa compound of Formula (I), wherein Z is —NR₃R₄. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (I),wherein Z is —NR₃R₄ and R₃ and R₄ are each independently hydrogen orsubstituted or unsubstituted alkyl. In another embodiment of any of theaforementioned embodiments is a compound of Formula (I), wherein Z is—NR₃R₄ and R₃ and R₄ are each independently hydrogen or methyl. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (I), wherein Z is —NR₃R₄ and R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (I), wherein Z is —NR₃R₄ and R₃ is hydrogen orR₄ is methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (I), wherein n is 1. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (I), wherein n is 2. In another embodiment of any of theaforementioned embodiments is a compound of Formula (I), wherein n is 3.In another embodiment of any of the aforementioned embodiments is acompound of Formula (I), wherein n is 4. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (I), wherein nis 5. In another embodiment of any of the aforementioned embodiments isa compound of Formula (I), wherein n is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (I), whereinn is 7. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (I), wherein n is 8. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (I),wherein n is 9. In another embodiment of any of the aforementionedembodiments is a compound of Formula (I), wherein n is 10.

In another embodiment, described herein is a compound having thestructure of Formula (II):

wherein:

Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolichydroxyl group is replaced by a covalent bond to—C(O)—N(R₅)—(C(R₁)(R₂))_(n)—Z;

Z is —NR₃R₄;

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group, or R₁ and R₅groups on adjacent atoms, together with the atoms to which they areattached, form a substituted or unsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

n is an integer from 2 to 10; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (II), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is substituted or unsubstituted alkyl. Insome embodiments is a compound of Formula (II), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl or alkylsubstituted with one or more groups selected from halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In someembodiments is a compound of Formula (II), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkylor alkyl substituted with one or more groups selected from halogen, —CN,—NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some embodiments is a compound of Formula (II), wherein Y is

R₆ is alkoxy; J is-NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl.

In some embodiments is a compound of Formula (II), wherein Y is

In some embodiments is a compound of Formula (II), wherein Y is

In some embodiments is a compound of Formula (II), wherein Y is

In some embodiments is a compound of Formula (II), wherein Y is

In some embodiments is a compound of Formula (II), wherein Y is

In some embodiments is a compound of Formula (II), wherein Y is

In some embodiments is a compound of Formula (II), wherein R₅ is H. Insome embodiments is a compound of Formula (II), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (II), wherein R₅ is unsubstituted alkyl. In some embodiments isa compound of Formula (II), wherein R₅ is substituted alkyl. In someembodiments is a compound of Formula (II), wherein R₅ is substituted orunsubstituted aryl. In some embodiments is a compound of Formula (II),wherein R₅ is substituted phenyl. In some embodiments is a compound ofFormula (II), wherein R₅ is unsubstituted phenyl. In some embodiments isa compound of Formula (II), wherein R₅ is —CH₃. In some embodiments is acompound of Formula (II), wherein R₅ is —CH₂CH₃. In some embodiments isa compound of Formula (II), wherein R₅ is —CH₂CH₂NH₂. In someembodiments is a compound of Formula (II), wherein R₅ is—CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula (II),wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any of theaforementioned embodiments is a compound of Formula (II), wherein eachR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (II),wherein each R₁ and R₂ are each independently hydrogen, or substitutedor unsubstituted alkyl. In another embodiment of any of theaforementioned embodiments is a compound of Formula (II), wherein eachR₁ and R₂ are hydrogen. In another embodiment of any of theaforementioned embodiments is a compound of Formula (II), wherein two R₁or R₂ groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a substituted or unsubstituted cycloalkylgroup. In another embodiment of any of the aforementioned embodiments isa compound of Formula (II), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (II), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (II), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (II), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (II), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (II), wherein n is 2. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (II), whereinn is 3. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (II), wherein n is 4. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (II),wherein n is 5. In another embodiment of any of the aforementionedembodiments is a compound of Formula (II), wherein n is 6. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (II), wherein n is 7. In another embodiment of any of theaforementioned embodiments is a compound of Formula (II), wherein n is8. In another embodiment of any of the aforementioned embodiments is acompound of Formula (II), wherein n is 9. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (II), whereinn is 10.

In another embodiment, described herein is a compound having thestructure of Formula (IIa):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group, or R₁ and R₅groups on adjacent atoms, together with the atoms to which they areattached, form a substituted or unsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIa), wherein R₅ is H. Insome embodiments is a compound of Formula (IIa), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IIa), wherein R₅ is unsubstituted alkyl. In some embodiments isa compound of Formula (IIa), wherein R₅ is substituted alkyl. In someembodiments is a compound of Formula (IIa), wherein R₅ is substituted orunsubstituted aryl. In some embodiments is a compound of Formula (IIa),wherein R₅ is substituted phenyl. In some embodiments is a compound ofFormula (IIa), wherein R₅ is unsubstituted phenyl. In some embodimentsis a compound of Formula (IIa), wherein R₅ is —CH₃. In some embodimentsis a compound of Formula (IIa), wherein R₅ is —CH₂CH₃. In someembodiments is a compound of Formula (IIa), wherein R₅ is —CH₂CH₂NH₂. Insome embodiments is a compound of Formula (IIa), wherein R₅ is—CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula (IIa),wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIa), wherein eachR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIa),wherein each R₁ and R₂ are each independently hydrogen, or substitutedor unsubstituted alkyl. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIa), wherein eachR₁ and R₂ are hydrogen. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIa), wherein eachR₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIa), wherein two R₁ or R₂ groupson adjacent carbon atoms, together with the carbon atoms to which theyare attached, form a substituted or unsubstituted cycloalkyl group. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IIa), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIa), whereinR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIa), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIa), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperazine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIa), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIa), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIa), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIa), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIa), wherein p is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIa),wherein p is 2. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIa), wherein p is 3. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIa), wherein p is 4. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIa), wherein p is5. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIa), wherein p is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIa),wherein p is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIa), wherein p is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIa), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIaa):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or R₁ and R₅ groups together withthe atoms to which they are attached, form a substituted orunsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIaa), wherein R₅ is H. Insome embodiments is a compound of Formula (IIaa), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IIaa), wherein R₅ is unsubstituted alkyl. In some embodimentsis a compound of Formula (IIaa), wherein R₅ is substituted alkyl. Insome embodiments is a compound of Formula (IIaa), wherein R₅ issubstituted or unsubstituted aryl. In some embodiments is a compound ofFormula (IIaa), wherein R₅ is substituted phenyl. In some embodiments isa compound of Formula (IIaa), wherein R₅ is unsubstituted phenyl. Insome embodiments is a compound of Formula (IIaa), wherein R₅ is —CH₃. Insome embodiments is a compound of Formula (IIaa), wherein R₅ is —CH₂CH₃.In some embodiments is a compound of Formula (IIaa), wherein R₅ is—CH₂CH₂NH₂. In some embodiments is a compound of Formula (IIaa), whereinR₅ is —CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula(IIaa), wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIaa), whereinR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIaa),wherein R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIaa), wherein R₁ and R₂ arehydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIaa), wherein R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IIaa), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIaa), whereinR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIaa), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIaa), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperazine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIaa), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIaa), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIaa), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIaa), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIaa), wherein p is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIaa),wherein p is 2. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIaa), wherein p is 3. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIaa), wherein p is 4. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIaa), wherein p is5. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIaa), wherein p is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIaa),wherein p is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIaa), wherein p is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIaa), wherein p is 9.

In some embodiments is a compound of Formula (IIaa), having thestructure:

wherein R₄ is hydrogen or methyl; and p is an integer from 1 to 9.

In some embodiments is a compound of Formula (IIaa), having thestructure:

wherein R₄ is hydrogen or methyl; and p is an integer from 1 to 2.

In some embodiments is a compound of Formula (IIaa), having thestructure:

wherein R₄ is hydrogen or methyl; and p is 1.

In some embodiments is a compound of Formula (IIaa), having thestructure:

wherein R₄ is hydrogen or methyl; and p is 2.

In some embodiments is a compound of Formula (IIaa), having thestructure:

wherein R₄ is hydrogen or methyl; and p is an integer from 1 to 9.

In some embodiments is a compound of Formula (IIaa), having thestructure:

wherein R₄ is hydrogen or methyl; and p is an integer from 1 to 2.

In some embodiments is a compound of Formula (IIaa), having thestructure:

wherein R₄ is hydrogen or methyl; and p is 1.

In some embodiments is a compound of Formula (IIaa), having thestructure:

wherein R₄ is hydrogen or methyl; and p is 2.

In another embodiment, described herein is a compound having thestructure of Formula (IIb):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group, or R₁ and R₅groups on adjacent atoms, together with the atoms to which they areattached, form a substituted or unsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIb), wherein R₅ is H. Insome embodiments is a compound of Formula (IIb), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IIb), wherein R₅ is unsubstituted alkyl. In some embodiments isa compound of Formula (IIb), wherein R₅ is substituted alkyl. In someembodiments is a compound of Formula (IIb), wherein R₅ is substituted orunsubstituted aryl. In some embodiments is a compound of Formula (IIb),wherein R₅ is substituted phenyl. In some embodiments is a compound ofFormula (IIb), wherein R₅ is unsubstituted phenyl. In some embodimentsis a compound of Formula (IIb), wherein R₅ is —CH₃. In some embodimentsis a compound of Formula (IIb), wherein R₅ is —CH₂CH₃. In someembodiments is a compound of Formula (IIb), wherein R₅ is —CH₂CH₂NH₂. Insome embodiments is a compound of Formula (IIb), wherein R₅ is—CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula (IIb),wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIb), wherein eachR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIb),wherein each R₁ and R₂ are each independently hydrogen, or substitutedor unsubstituted alkyl. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIb), wherein eachR₁ and R₂ are hydrogen. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIb), wherein eachR₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIb), wherein two R₁ or R₂ groupson adjacent carbon atoms, together with the carbon atoms to which theyare attached, form a substituted or unsubstituted cycloalkyl group. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IIb), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIb), whereinR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIb), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIb), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperazine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIb), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIb), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIb), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIb), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIb), wherein p is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIb),wherein p is 2. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIb), wherein p is 3. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIb), wherein p is 4. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIb), wherein p is5. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIb), wherein p is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIb),wherein p is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIb), wherein p is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIb), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIbb):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or R₁ and R₅ groups together withthe atoms to which they are attached, form a substituted orunsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIbb), wherein R₅ is H. Insome embodiments is a compound of Formula (IIbb), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IIbb), wherein R₅ is unsubstituted alkyl. In some embodimentsis a compound of Formula (IIbb), wherein R₅ is substituted alkyl. Insome embodiments is a compound of Formula (IIbb), wherein R₅ issubstituted or unsubstituted aryl. In some embodiments is a compound ofFormula (IIbb), wherein R₅ is substituted phenyl. In some embodiments isa compound of Formula (IIbb), wherein R₅ is unsubstituted phenyl. Insome embodiments is a compound of Formula (IIbb), wherein R₅ is —CH₃. Insome embodiments is a compound of Formula (IIbb), wherein R₅ is —CH₂CH₃.In some embodiments is a compound of Formula (IIbb), wherein R₅ is—CH₂CH₂NH₂. In some embodiments is a compound of Formula (IIbb), whereinR₅ is —CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula(IIbb), wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIbb), whereinR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIbb),wherein R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIbb), wherein R₁ and R₂ arehydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIbb), wherein R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IIbb), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIbb), whereinR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIbb), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIbb), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperazine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIbb), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIbb), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIbb), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIbb), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIbb), wherein p is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIbb),wherein p is 2. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIbb), wherein p is 3. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIbb), wherein p is 4. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIbb), wherein p is5. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIbb), wherein p is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIbb),wherein p is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIbb), wherein p is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIbb), wherein p is 9.

In some embodiments is a compound of Formula (IIbb), having thestructure:

wherein R₄ is hydrogen or methyl; and p is an integer from 1 to 9.

In some embodiments is a compound of Formula (IIbb), having thestructure:

wherein R₄ is hydrogen or methyl; and p is an integer from 1 to 2.

In some embodiments is a compound of Formula (IIbb), having thestructure:

wherein R₄ is hydrogen or methyl; and p is 1.

In some embodiments is a compound of Formula (IIbb), having thestructure:

wherein R₄ is hydrogen or methyl; and p is 2.

In some embodiments is a compound of Formula (IIbb), having thestructure:

wherein R₄ is hydrogen or methyl; and p is an integer from 1 to 9.

In some embodiments is a compound of Formula (IIbb), having thestructure:

wherein R₄ is hydrogen or methyl; and p is an integer from 1 to 2.

In some embodiments is a compound of Formula (IIbb), having thestructure:

wherein R₄ is hydrogen or methyl; and p is 1.

In some embodiments is a compound of Formula (IIbb), having thestructure:

wherein R₄ is hydrogen or methyl; and p is 2.

In another embodiment, described herein is a compound having thestructure of Formula (IIc):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group, or R₁ and R₅groups on adjacent atoms, together with the atoms to which they areattached, form a substituted or unsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIc), wherein R₅ is H. Insome embodiments is a compound of Formula (IIc), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IIc), wherein R₅ is unsubstituted alkyl. In some embodiments isa compound of Formula (IIc), wherein R₅ is substituted alkyl. In someembodiments is a compound of Formula (IIc), wherein R₅ is substituted orunsubstituted aryl. In some embodiments is a compound of Formula (IIc),wherein R₅ is substituted phenyl. In some embodiments is a compound ofFormula (IIc), wherein R₅ is unsubstituted phenyl. In some embodimentsis a compound of Formula (IIc), wherein R₅ is —CH₃. In some embodimentsis a compound of Formula (IIc), wherein R₅ is —CH₂CH₃. In someembodiments is a compound of Formula (IIc), wherein R₅ is —CH₂CH₂NH₂. Insome embodiments is a compound of Formula (IIc), wherein R₅ is—CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula (IIc),wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIc), wherein eachR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIc),wherein each R₁ and R₂ are each independently hydrogen, or substitutedor unsubstituted alkyl. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIc), wherein eachR₁ and R₂ are hydrogen. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIc), wherein eachR₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIc), wherein two R₁ or R₂ groupson adjacent carbon atoms, together with the carbon atoms to which theyare attached, form a substituted or unsubstituted cycloalkyl group. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IIc), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIc), whereinR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIc), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIc), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperazine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIc), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIc), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIc), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIc), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIc), wherein p is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIc),wherein p is 2. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIc), wherein p is 3. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIc), wherein p is 4. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIc), wherein p is5. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIc), wherein p is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIc),wherein p is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIc), wherein p is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIc), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIcc):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or R₁ and R₅ groups together withthe atoms to which they are attached, form a substituted orunsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIcc), wherein R₅ is H. Insome embodiments is a compound of Formula (IIcc), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IIcc), wherein R₅ is unsubstituted alkyl. In some embodimentsis a compound of Formula (IIcc), wherein R₅ is substituted alkyl. Insome embodiments is a compound of Formula (IIcc), wherein R₅ issubstituted or unsubstituted aryl. In some embodiments is a compound ofFormula (IIcc), wherein R₅ is substituted phenyl. In some embodiments isa compound of Formula (IIcc), wherein R₅ is unsubstituted phenyl. Insome embodiments is a compound of Formula (IIcc), wherein R₅ is —CH₃. Insome embodiments is a compound of Formula (IIcc), wherein R₅ is —CH₂CH₃.In some embodiments is a compound of Formula (IIcc), wherein R₅ is—CH₂CH₂NH₂. In some embodiments is a compound of Formula (IIcc), whereinR₅ is —CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula(IIcc), wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIcc), whereinR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIcc),wherein R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIcc), wherein R₁ and R₂ arehydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIcc), wherein R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IIcc), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIcc), whereinR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIcc), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIcc), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperazine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIcc), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIcc), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIcc), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIcc), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIcc), wherein p is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIcc),wherein p is 2. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIcc), wherein p is 3. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIcc), wherein p is 4. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIcc), wherein p is5. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIcc), wherein p is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIcc),wherein p is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIcc), wherein p is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIcc), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IId):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group, or R₁ and R₅groups on adjacent atoms, together with the atoms to which they areattached, form a substituted or unsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IId), wherein R₅ is H. Insome embodiments is a compound of Formula (IId), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IId), wherein R₅ is unsubstituted alkyl. In some embodiments isa compound of Formula (IId), wherein R₅ is substituted alkyl. In someembodiments is a compound of Formula (IId), wherein R₅ is substituted orunsubstituted aryl. In some embodiments is a compound of Formula (IId),wherein R₅ is substituted phenyl. In some embodiments is a compound ofFormula (IId), wherein R₅ is unsubstituted phenyl. In some embodimentsis a compound of Formula (IId), wherein R₅ is —CH₃. In some embodimentsis a compound of Formula (IId), wherein R₅ is —CH₂CH₃. In someembodiments is a compound of Formula (IId), wherein R₅ is —CH₂CH₂NH₂. Insome embodiments is a compound of Formula (IId), wherein R₅ is—CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula (IId),wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any of theaforementioned embodiments is a compound of Formula (IId), wherein eachR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IId),wherein each R₁ and R₂ are each independently hydrogen, or substitutedor unsubstituted alkyl. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IId), wherein eachR₁ and R₂ are hydrogen. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IId), wherein eachR₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IId), wherein two R₁ or R₂ groupson adjacent carbon atoms, together with the carbon atoms to which theyare attached, form a substituted or unsubstituted cycloalkyl group. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IId), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IId), whereinR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IId), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IId), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperazine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IId), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IId), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IId), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IId), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (IId), wherein p is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IId),wherein p is 2. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IId), wherein p is 3. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IId), wherein p is 4. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IId), wherein p is5. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IId), wherein p is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IId),wherein p is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IId), wherein p is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IId), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIdd):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or R₁ and R₅ groups together withthe atoms to which they are attached, form a substituted orunsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIdd), wherein R₅ is H. Insome embodiments is a compound of Formula (IIdd), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IIdd), wherein R₅ is unsubstituted alkyl. In some embodimentsis a compound of Formula (IIdd), wherein R₅ is substituted alkyl. Insome embodiments is a compound of Formula (IIdd), wherein R₅ issubstituted or unsubstituted aryl. In some embodiments is a compound ofFormula (IIdd), wherein R₅ is substituted phenyl. In some embodiments isa compound of Formula (IIdd), wherein R₅ is unsubstituted phenyl. Insome embodiments is a compound of Formula (IIdd), wherein R₅ is —CH₃. Insome embodiments is a compound of Formula (IIdd), wherein R₅ is —CH₂CH₃.In some embodiments is a compound of Formula (IIdd), wherein R₅ is—CH₂CH₂NH₂. In some embodiments is a compound of Formula (IIdd), whereinR₅ is —CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula(IIdd), wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIdd), whereinR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIdd),wherein R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIdd), wherein R₁ and R₂ arehydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIdd), wherein R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IIdd), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIdd), whereinR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIdd), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIdd), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperazine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIdd), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIdd), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIdd), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIdd), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIdd), wherein p is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIdd),wherein p is 2. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIdd), wherein p is 3. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIdd), wherein p is 4. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIdd), wherein p is5. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIdd), wherein p is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIdd),wherein p is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIdd), wherein p is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIdd), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIe):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group, or R₁ and R₅groups on adjacent atoms, together with the atoms to which they areattached, form a substituted or unsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIe), wherein R₅ is H. Insome embodiments is a compound of Formula (IIe), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IIe), wherein R₅ is unsubstituted alkyl. In some embodiments isa compound of Formula (IIe), wherein R₅ is substituted alkyl. In someembodiments is a compound of Formula (IIe), wherein R₅ is substituted orunsubstituted aryl. In some embodiments is a compound of Formula (IIe),wherein R₅ is substituted phenyl. In some embodiments is a compound ofFormula (IIe), wherein R₅ is unsubstituted phenyl. In some embodimentsis a compound of Formula (IIe), wherein R₅ is —CH₃. In some embodimentsis a compound of Formula (IIe), wherein R₅ is —CH₂CH₃. In someembodiments is a compound of Formula (IIe), wherein R₅ is —CH₂CH₂NH₂. Insome embodiments is a compound of Formula (IIe), wherein R₅ is—CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula (IIe),wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIe), wherein eachR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIe),wherein each R₁ and R₂ are each independently hydrogen, or substitutedor unsubstituted alkyl. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIe), wherein eachR₁ and R₂ are hydrogen. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIe), wherein eachR₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIe), wherein two R₁ or R₂ groupson adjacent carbon atoms, together with the carbon atoms to which theyare attached, form a substituted or unsubstituted cycloalkyl group. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IIe), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIa), whereinR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIe), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIe), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperazine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIe), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIe), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIe), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIe), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIe), wherein p is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIe),wherein p is 2. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIe), wherein p is 3. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIe), wherein p is 4. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIe), wherein p is5. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIe), wherein p is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIe),wherein p is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIe), wherein p is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIe), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIee):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or R₁ and R₅ groups together withthe atoms to which they are attached, form a substituted orunsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIee), wherein R₅ is H. Insome embodiments is a compound of Formula (IIee), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IIee), wherein R₅ is unsubstituted alkyl. In some embodimentsis a compound of Formula (IIee), wherein R₅ is substituted alkyl. Insome embodiments is a compound of Formula (IIee), wherein R₅ issubstituted or unsubstituted aryl. In some embodiments is a compound ofFormula (IIee), wherein R₅ is substituted phenyl. In some embodiments isa compound of Formula (IIee), wherein R₅ is unsubstituted phenyl. Insome embodiments is a compound of Formula (IIee), wherein R₅ is —CH₃. Insome embodiments is a compound of Formula (IIee), wherein R₅ is —CH₂CH₃.In some embodiments is a compound of Formula (IIee), wherein R₅ is—CH₂CH₂NH₂. In some embodiments is a compound of Formula (IIee), whereinR₅ is —CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula(IIee), wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIee), whereinR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIee),wherein R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIee), wherein R₁ and R₂ arehydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIee), wherein R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IIee), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIee), whereinR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIee), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIee), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperazine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIee), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIee), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIee), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIee), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIee), wherein p is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIee),wherein p is 2. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIee), wherein p is 3. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIee), wherein p is 4. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIee), wherein p is5. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIee), wherein p is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIee),wherein p is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIee), wherein p is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIee), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIf):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group, or R₁ and R₅groups on adjacent atoms, together with the atoms to which they areattached, form a substituted or unsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIf), wherein R₅ is H. Insome embodiments is a compound of Formula (IIf), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IIf), wherein R₅ is unsubstituted alkyl. In some embodiments isa compound of Formula (IIf), wherein R₅ is substituted alkyl. In someembodiments is a compound of Formula (IIf), wherein R₅ is substituted orunsubstituted aryl. In some embodiments is a compound of Formula (IIf),wherein R₅ is substituted phenyl. In some embodiments is a compound ofFormula (IIf), wherein R₅ is unsubstituted phenyl. In some embodimentsis a compound of Formula (IIf), wherein R₅ is —CH₃. In some embodimentsis a compound of Formula (IIf), wherein R₅ is —CH₂CH₃. In someembodiments is a compound of Formula (IIf), wherein R₅ is —CH₂CH₂NH₂. Insome embodiments is a compound of Formula (IIf), wherein R₅ is—CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula (IIf),wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIf), wherein eachR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIf),wherein each R₁ and R₂ are each independently hydrogen, or substitutedor unsubstituted alkyl. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIf), wherein eachR₁ and R₂ are hydrogen. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIf), wherein eachR₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIf), wherein two R₁ or R₂ groupson adjacent carbon atoms, together with the carbon atoms to which theyare attached, form a substituted or unsubstituted cycloalkyl group. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IIf), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIf), whereinR₃ and R₄ are each independently hydrogen or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIf), wherein R₁ and R₅ groups onadjacent atoms, together with the atoms to which they are attached, forma substituted or unsubstituted heterocycloalkyl group, wherein theheterocycloalkyl group is a substituted or unsubstituted pyrrolidinering. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIf), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group, wherein the heterocycloalkylgroup is a substituted or unsubstituted piperidine ring. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIf), wherein R₁ and R₅ groups on adjacent atoms, together withthe atoms to which they are attached, form a substituted orunsubstituted heterocycloalkyl group, wherein the heterocycloalkyl groupis a substituted or unsubstituted piperazine ring. In another embodimentof any of the aforementioned embodiments is a compound of Formula (IIf),wherein R₃ and R₄ are each independently hydrogen or methyl. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIf), wherein R₃ and R₄ are each hydrogen. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIf), wherein R₃ is hydrogen or R₄ is methyl. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIf), wherein p is 1. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIf), wherein p is2. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIf), wherein p is 3. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIf),wherein p is 4. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIf), wherein p is 5. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIf), wherein p is 6. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIf), wherein p is7. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIf), wherein p is 8. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIf),wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIff):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or R₁ and R₅ groups together withthe atoms to which they are attached, form a substituted orunsubstituted heterocycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIff), wherein R₅ is H. Insome embodiments is a compound of Formula (IIff), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IIff), wherein R₅ is unsubstituted alkyl. In some embodimentsis a compound of Formula (IIff), wherein R₅ is substituted alkyl. Insome embodiments is a compound of Formula (IIff), wherein R₅ issubstituted or unsubstituted aryl. In some embodiments is a compound ofFormula (IIff), wherein R₅ is substituted phenyl. In some embodiments isa compound of Formula (IIff), wherein R₅ is unsubstituted phenyl. Insome embodiments is a compound of Formula (IIff), wherein R₅ is —CH₃. Insome embodiments is a compound of Formula (IIff), wherein R₅ is —CH₂CH₃.In some embodiments is a compound of Formula (IIff), wherein R₅ is—CH₂CH₂NH₂. In some embodiments is a compound of Formula (IIff), whereinR₅ is —CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula(IIff), wherein R₅ is —CH₂CH₂NH(CH₃). In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIff), whereinR₁ and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIff),wherein R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIff), wherein R₁ and R₂ arehydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIff), wherein R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (IIff), wherein R₁ and R₅ groups on adjacent atoms,together with the atoms to which they are attached, form a substitutedor unsubstituted heterocycloalkyl group. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (IIff), whereinR₁ and R₅ groups on adjacent atoms, together with the atoms to whichthey are attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted pyrrolidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIff), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperidine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIff), wherein R₁and R₅ groups on adjacent atoms, together with the atoms to which theyare attached, form a substituted or unsubstituted heterocycloalkylgroup, wherein the heterocycloalkyl group is a substituted orunsubstituted piperazine ring. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIff), wherein R₃and R₄ are each independently hydrogen or substituted or unsubstitutedalkyl. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIff), wherein R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIff), wherein R₃ and R₄ are eachhydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IIff), wherein R₃ is hydrogen or R₄ is methyl.In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIff), wherein p is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIff),wherein p is 2. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIff), wherein p is 3. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIff), wherein p is 4. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIff), wherein p is5. In another embodiment of any of the aforementioned embodiments is acompound of Formula (IIff), wherein p is 6. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (IIff),wherein p is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIff), wherein p is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIff), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (III):

wherein:

Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolichydroxyl group is replaced by a covalent bond to—C(O)—C(R₁)(R₂)—(C(R₁)(R₂))_(n)—Z;

Z is —NR₃R₄ or —CO₂H;

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group;

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; and

n is an integer from 1 to 10; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (III), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is substituted or unsubstituted alkyl. Insome embodiments is a compound of Formula (III), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl or alkylsubstituted with one or more groups selected from halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In someembodiments is a compound of Formula (III), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkylor alkyl substituted with one or more groups selected from halogen, —CN,—NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some embodiments is a compound of Formula (III), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl.

In some embodiments is a compound of Formula (III), wherein Y is

In some embodiments is a compound of Formula (III), wherein Y is

In some embodiments is a compound of Formula (III),

In some embodiments is a compound of Formula (III), wherein Y is

In some embodiments is a compound of Formula (III), wherein Y is

In some embodiments is a compound of Formula (III), wherein Y is

In another embodiment of any of the aforementioned embodiments is acompound of Formula (III), wherein each R₁ and R₂ are each independentlyhydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (III), wherein each R₁ and R₂ areeach independently hydrogen, or substituted or unsubstituted alkyl. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (III), wherein each R₁ and R₂ are hydrogen. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (III), wherein two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (III), wherein R₃ and R₄ are each independently hydrogen orsubstituted or unsubstituted alkyl. In another embodiment of any of theaforementioned embodiments is a compound of Formula (III), wherein R₃and R₄ are each independently hydrogen or methyl. In another embodimentof any of the aforementioned embodiments is a compound of Formula (III),wherein R₃ and R₄ are each hydrogen. In another embodiment of any of theaforementioned embodiments is a compound of Formula (III), wherein R₃ ishydrogen or R₄ is methyl. In another embodiment of any of theaforementioned embodiments is a compound of Formula (III), wherein n is2. In another embodiment of any of the aforementioned embodiments is acompound of Formula (III), wherein n is 3. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (III),wherein n is 4. In another embodiment of any of the aforementionedembodiments is a compound of Formula (III), wherein n is 5. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (III), wherein n is 6. In another embodiment of any of theaforementioned embodiments is a compound of Formula (III), wherein n is7. In another embodiment of any of the aforementioned embodiments is acompound of Formula (III), wherein n is 8. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (III),wherein n is 9. In another embodiment of any of the aforementionedembodiments is a compound of Formula (III), wherein n is 10.

In another embodiment, described herein is a compound having thestructure of Formula (IIIa):

wherein:

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group; and

p is an integer from 0 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIIa), wherein each R₁ andR₂ are each independently hydrogen, substituted or unsubstituted alkyl,or substituted or unsubstituted aryl. In some embodiments is a compoundof Formula (IIIa), wherein each R₁ and R₂ are each independentlyhydrogen, or substituted or unsubstituted alkyl. In some embodiments isa compound of Formula (IIIa), wherein each R₁ and R₂ are hydrogen. Insome embodiments is a compound of Formula (IIIa), wherein each R₁ and R₂are each independently hydrogen, or substituted or unsubstituted alkyl.In some embodiments is a compound of Formula (IIIa), wherein two R₁ orR₂ groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a substituted or unsubstituted cycloalkylgroup. In some embodiments is a compound of Formula (IIIa), wherein p is0. In some embodiments is a compound of Formula (IIIa), wherein p is 1.In some embodiments is a compound of Formula (IIIa), wherein p is 2. Insome embodiments is a compound of Formula (IIIa), wherein p is 3. Insome embodiments is a compound of Formula (IIIa), wherein p is 4. Insome embodiments is a compound of Formula (IIIa), wherein p is 5. Insome embodiments is a compound of Formula (IIIa), wherein p is 6. Insome embodiments is a compound of Formula (IIIa), wherein p is 7. Insome embodiments is a compound of Formula (IIIa), wherein p is 8. Insome embodiments is a compound of Formula (IIIa), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIIaa):

wherein:

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIIaa), wherein each R₁and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In some embodiments is acompound of Formula (IIIaa), wherein each R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. In someembodiments is a compound of Formula (IIIaa), wherein each R₁ and R₂ arehydrogen. In some embodiments is a compound of Formula (IIIaa), whereineach R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In some embodiments is a compound of Formula(IIIaa), wherein two R₁ or R₂ groups on adjacent carbon atoms, togetherwith the carbon atoms to which they are attached, form a substituted orunsubstituted cycloalkyl group. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIaa), wherein pis 1. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIaa), wherein p is 2. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIaa),wherein p is 3. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIaa), wherein p is 4. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIIaa), wherein p is 5. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIaa), wherein pis 6. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIaa), wherein p is 7. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIaa),wherein p is 8. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIaa), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIIb):

wherein:

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIIb), wherein each R₁ andR₂ are each independently hydrogen, substituted or unsubstituted alkyl,or substituted or unsubstituted aryl. In some embodiments is a compoundof Formula (IIIb), wherein each R₁ and R₂ are each independentlyhydrogen, or substituted or unsubstituted alkyl. In some embodiments isa compound of Formula (IIIb), wherein each R₁ and R₂ are hydrogen. Insome embodiments is a compound of Formula (IIIb), wherein each R₁ and R₂are each independently hydrogen, or substituted or unsubstituted alkyl.In some embodiments is a compound of Formula (IIIb), wherein two R₁ orR₂ groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a substituted or unsubstituted cycloalkylgroup. In some embodiments is a compound of Formula (IIIb), wherein p is0. In some embodiments is a compound of Formula (IIIb), wherein p is 1.In some embodiments is a compound of Formula (IIIb), wherein p is 2. Insome embodiments is a compound of Formula (IIIb), wherein p is 3. Insome embodiments is a compound of Formula (IIIb), wherein p is 4. Insome embodiments is a compound of Formula (IIIb), wherein p is 5. Insome embodiments is a compound of Formula (IIIb), wherein p is 6. Insome embodiments is a compound of Formula (IIIb), wherein p is 7. Insome embodiments is a compound of Formula (IIIb), wherein p is 8. Insome embodiments is a compound of Formula (IIIb), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIIbb):

wherein:

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIIbb), wherein each R₁and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In some embodiments is acompound of Formula (IIIbb), wherein each R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. In someembodiments is a compound of Formula (IIIbb), wherein each R₁ and R₂ arehydrogen. In some embodiments is a compound of Formula (IIIbb), whereineach R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In some embodiments is a compound of Formula(IIIbb), wherein two R₁ or R₂ groups on adjacent carbon atoms, togetherwith the carbon atoms to which they are attached, form a substituted orunsubstituted cycloalkyl group. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIbb), wherein pis 1. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIbb), wherein p is 2. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIbb),wherein p is 3. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIbb), wherein p is 4. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIIbb), wherein p is 5. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIbb), wherein pis 6. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIbb), wherein p is 7. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIbb),wherein p is 8. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIbb), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIIc):

wherein:

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group; and

p is an integer from 0 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIIc), wherein each R₁ andR₂ are each independently hydrogen, substituted or unsubstituted alkyl,or substituted or unsubstituted aryl. In some embodiments is a compoundof Formula (IIIc), wherein each R₁ and R₂ are each independentlyhydrogen, or substituted or unsubstituted alkyl. In some embodiments isa compound of Formula (IIIc), wherein each R₁ and R₂ are hydrogen. Insome embodiments is a compound of Formula (IIIc), wherein each R₁ and R₂are each independently hydrogen, or substituted or unsubstituted alkyl.In some embodiments is a compound of Formula (IIIc), wherein two R₁ orR₂ groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a substituted or unsubstituted cycloalkylgroup. In some embodiments is a compound of Formula (IIIc), wherein p is0. In some embodiments is a compound of Formula (IIIc), wherein p is 1.In some embodiments is a compound of Formula (IIIc), wherein p is 2. Insome embodiments is a compound of Formula (IIIc), wherein p is 3. Insome embodiments is a compound of Formula (IIIc), wherein p is 4. Insome embodiments is a compound of Formula (IIIc), wherein p is 5. Insome embodiments is a compound of Formula (IIIc), wherein p is 6. Insome embodiments is a compound of Formula (IIIc), wherein p is 7. Insome embodiments is a compound of Formula (IIIc), wherein p is 8. Insome embodiments is a compound of Formula (IIIc), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIIcc):

wherein:

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIIcc), wherein each R₁and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In some embodiments is acompound of Formula (IIIcc), wherein each R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. In someembodiments is a compound of Formula (IIIcc), wherein each R₁ and R₂ arehydrogen. In some embodiments is a compound of Formula (IIIcc), whereineach R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In some embodiments is a compound of Formula(IIIcc), wherein two R₁ or R₂ groups on adjacent carbon atoms, togetherwith the carbon atoms to which they are attached, form a substituted orunsubstituted cycloalkyl group. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIcc), wherein pis 1. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIcc), wherein p is 2. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIcc),wherein p is 3. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIcc), wherein p is 4. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIIcc), wherein p is 5. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIcc), wherein pis 6. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIcc), wherein p is 7. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIcc),wherein p is 8. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIcc), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIId):

wherein:

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group; and

p is an integer from 0 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIId), wherein each R₁ andR₂ are each independently hydrogen, substituted or unsubstituted alkyl,or substituted or unsubstituted aryl. In some embodiments is a compoundof Formula (IIId), wherein each R₁ and R₂ are each independentlyhydrogen, or substituted or unsubstituted alkyl. In some embodiments isa compound of Formula (IIId), wherein each R₁ and R₂ are hydrogen. Insome embodiments is a compound of Formula (IIId), wherein each R₁ and R₂are each independently hydrogen, or substituted or unsubstituted alkyl.In some embodiments is a compound of Formula (IIId), wherein two R₁ orR₂ groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a substituted or unsubstituted cycloalkylgroup. In some embodiments is a compound of Formula (IIId), wherein p is0. In some embodiments is a compound of Formula (IIId), wherein p is 1.In some embodiments is a compound of Formula (IIId), wherein p is 2. Insome embodiments is a compound of Formula (IIId), wherein p is 3. Insome embodiments is a compound of Formula (IIId), wherein p is 4. Insome embodiments is a compound of Formula (IIId), wherein p is 5. Insome embodiments is a compound of Formula (IIId), wherein p is 6. Insome embodiments is a compound of Formula (IIId), wherein p is 7. Insome embodiments is a compound of Formula (IIId), wherein p is 8. Insome embodiments is a compound of Formula (IIId), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIIdd):

wherein:

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIIdd), wherein each R₁and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In some embodiments is acompound of Formula (IIIdd), wherein each R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. In someembodiments is a compound of Formula (IIIdd), wherein each R₁ and R₂ arehydrogen. In some embodiments is a compound of Formula (IIIdd), whereineach R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In some embodiments is a compound of Formula(IIIdd), wherein two R₁ or R₂ groups on adjacent carbon atoms, togetherwith the carbon atoms to which they are attached, form a substituted orunsubstituted cycloalkyl group. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIdd), wherein pis 1. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIdd), wherein p is 2. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIdd),wherein p is 3. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIdd), wherein p is 4. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIIdd), wherein p is 5. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIdd), wherein pis 6. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIdd), wherein p is 7. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIdd),wherein p is 8. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIdd), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIIe):

wherein:

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group; and

p is an integer from 0 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIIe), wherein each R₁ andR₂ are each independently hydrogen, substituted or unsubstituted alkyl,or substituted or unsubstituted aryl. In some embodiments is a compoundof Formula (IIIe), wherein each R₁ and R₂ are each independentlyhydrogen, or substituted or unsubstituted alkyl. In some embodiments isa compound of Formula (IIIe), wherein each R₁ and R₂ are hydrogen. Insome embodiments is a compound of Formula (IIIe), wherein each R₁ and R₂are each independently hydrogen, or substituted or unsubstituted alkyl.In some embodiments is a compound of Formula (IIIe), wherein two R₁ orR₂ groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a substituted or unsubstituted cycloalkylgroup. In some embodiments is a compound of Formula (IIIe), wherein p is0. In some embodiments is a compound of Formula (IIIe), wherein p is 1.In some embodiments is a compound of Formula (IIIe), wherein p is 2. Insome embodiments is a compound of Formula (IIIe), wherein p is 3. Insome embodiments is a compound of Formula (IIIe), wherein p is 4. Insome embodiments is a compound of Formula (IIIe), wherein p is 5. Insome embodiments is a compound of Formula (IIIe), wherein p is 6. Insome embodiments is a compound of Formula (IIIe), wherein p is 7. Insome embodiments is a compound of Formula (IIIe), wherein p is 8. Insome embodiments is a compound of Formula (IIIe), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIIee):

wherein:

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIIee), wherein each R₁and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In some embodiments is acompound of Formula (IIIee), wherein each R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. In someembodiments is a compound of Formula (IIIee), wherein each R₁ and R₂ arehydrogen. In some embodiments is a compound of Formula (IIIee), whereineach R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In some embodiments is a compound of Formula(IIIee), wherein two R₁ or R₂ groups on adjacent carbon atoms, togetherwith the carbon atoms to which they are attached, form a substituted orunsubstituted cycloalkyl group. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIee), wherein pis 1. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIee), wherein p is 2. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIee),wherein p is 3. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIee), wherein p is 4. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIIee), wherein p is 5. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIee), wherein pis 6. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIee), wherein p is 7. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIee),wherein p is 8. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIee), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIIf):

wherein:

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group; and

p is an integer from 0 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIIf), wherein each R₁ andR₂ are each independently hydrogen, substituted or unsubstituted alkyl,or substituted or unsubstituted aryl. In some embodiments is a compoundof Formula (IIIf), wherein each R₁ and R₂ are each independentlyhydrogen, or substituted or unsubstituted alkyl. In some embodiments isa compound of Formula (IIIf), wherein each R₁ and R₂ are hydrogen. Insome embodiments is a compound of Formula (IIIf), wherein each R₁ and R₂are each independently hydrogen, or substituted or unsubstituted alkyl.In some embodiments is a compound of Formula (IIIf), wherein two R₁ orR₂ groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a substituted or unsubstituted cycloalkylgroup. In some embodiments is a compound of Formula (IIIf), wherein p is0. In some embodiments is a compound of Formula (IIIf), wherein p is 1.In some embodiments is a compound of Formula (IIIf), wherein p is 2. Insome embodiments is a compound of Formula (IIIf), wherein p is 3. Insome embodiments is a compound of Formula (IIIf), wherein p is 4. Insome embodiments is a compound of Formula (IIIf), wherein p is 5. Insome embodiments is a compound of Formula (IIIf), wherein p is 6. Insome embodiments is a compound of Formula (IIIf), wherein p is 7. Insome embodiments is a compound of Formula (IIIf), wherein p is 8. Insome embodiments is a compound of Formula (IIIf), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IIIff):

wherein:

each R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted acyl, or two R₁ or R₂ groups on adjacent carbon atoms,together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group; and

p is an integer from 1 to 9; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IIIff), wherein each R₁and R₂ are each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl. In some embodiments is acompound of Formula (IIIff), wherein each R₁ and R₂ are eachindependently hydrogen, or substituted or unsubstituted alkyl. In someembodiments is a compound of Formula (IIIff), wherein each R₁ and R₂ arehydrogen. In some embodiments is a compound of Formula (IIIff), whereineach R₁ and R₂ are each independently hydrogen, or substituted orunsubstituted alkyl. In some embodiments is a compound of Formula(IIIff), wherein two R₁ or R₂ groups on adjacent carbon atoms, togetherwith the carbon atoms to which they are attached, form a substituted orunsubstituted cycloalkyl group. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIff), wherein pis 1. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIff), wherein p is 2. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIff),wherein p is 3. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIff), wherein p is 4. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (IIIff), wherein p is 5. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IIIff), wherein pis 6. In another embodiment of any of the aforementioned embodiments isa compound of Formula (IIIff), wherein p is 7. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (IIIff),wherein p is 8. In another embodiment of any of the aforementionedembodiments is a compound of Formula (IIIff), wherein p is 9.

In another embodiment, described herein is a compound having thestructure of Formula (IV):

wherein:

Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolichydroxyl group is replaced by a covalent bond to

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl;

each R₁ is independently substituted or unsubstituted alkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted acyl;

R₂ is hydrogen, or substituted or unsubstituted alkyl; and

n is an integer from 0 to 4; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (IV), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is substituted or unsubstituted alkyl. Insome embodiments is a compound of Formula (IV), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl or alkylsubstituted with one or more groups selected from halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In someembodiments is a compound of Formula (IV), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkylor alkyl substituted with one or more groups selected from halogen, —CN,—NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some embodiments is a compound of Formula (IV), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl.

In some embodiments is a compound of Formula (IV), wherein Y is

In some embodiments is a compound of Formula (IV), wherein Y is

In some embodiments is a compound of Formula (IV), wherein Y is

In some embodiments is a compound of Formula (IV), wherein Y is

In some embodiments is a compound of Formula (IV), wherein Y is

In some embodiments is a compound of Formula (IV), wherein Y is

In some embodiments is a compound of Formula (IV), wherein R₅ is H. Insome embodiments is a compound of Formula (IV), wherein R₅ issubstituted or unsubstituted alkyl. In some embodiments is a compound ofFormula (IV), wherein R₅ is unsubstituted alkyl. In some embodiments isa compound of Formula (IV), wherein R₅ is substituted alkyl. In someembodiments is a compound of Formula (IV), wherein R₅ is substituted orunsubstituted aryl. In some embodiments is a compound of Formula (IV),wherein R₅ is substituted phenyl. In some embodiments is a compound ofFormula (IV), wherein R₅ is unsubstituted phenyl. In some embodiments isa compound of Formula (IV), wherein R₅ is —CH₃. In some embodiments is acompound of Formula (IV), wherein R₅ is —CH₂CH₃. In some embodiments isa compound of Formula (IV), wherein R₅ is —CH₂CH₂NH₂. In someembodiments is a compound of Formula (IV), wherein R₅ is—CH₂CH₂NH(alkyl). In some embodiments is a compound of Formula (IV),wherein R₅ is —CH₂CH₂NH(CH₃). In some embodiments is a compound ofFormula (IV), wherein n is 1 and R₁ is substituted or unsubstitutedalkyl. In some embodiments is a compound of Formula (IV), wherein n is 1and R₁ is unsubstituted alkyl. In some embodiments is a compound ofFormula (IV), wherein n is 0. In another embodiment of any of theaforementioned embodiments is a compound of Formula (IV), wherein R₂ ishydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IV), wherein R₂ is substituted orunsubstituted alkyl.

In another embodiment of any of the aforementioned embodiments is acompound of Formula (IV), wherein n is 0, R₂ is hydrogen and R₅ ishydrogen. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (IV), wherein n is 0, R₂ is hydrogen and R₅ ismethyl.

In another aspect, described herein is a compound having the structureof Formula (V):

wherein:

Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolichydroxyl group is replaced by a covalent bond to—C(O)—X—(C(R₁)(R₂))_(n)—Z;

X is —C(R₁)(R₂)—, —O—, —N(R₅)— or —S—;

n is an integer from 1 to 10;

Z is —NR₃R₄ or —CO₂H;

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or R₁ and R₂ together with thecarbon atom to which they are attached form a substituted orunsubstituted cycloalkyl group, or two R₁ or R₂ groups on adjacentcarbon atoms, together with the carbon atoms to which they are attached,form a substituted or unsubstituted cycloalkyl group, or R₁ and R₅groups on adjacent atoms, together with the atoms to which they areattached, form a substituted or unsubstituted heterocycloalkyl group;and

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (V), wherein Z is —NR₃R₄.In other embodiments is a compound of Formula (V), wherein Z is —CO₂H.

In some embodiments is a compound of Formula (V), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is substituted or unsubstituted alkyl. Insome embodiments is a compound of Formula (V), wherein Y is

R₆ is independently selected from hydrogen, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone; J is—NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl or alkylsubstituted with one or more groups selected from halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl,cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In someembodiments is a compound of Formula (V), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkylor alkyl substituted with one or more groups selected from halogen, —CN,—NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some embodiments is a compound of Formula (V), wherein Y is

R₆ is alkoxy; J is —NHC(O)R₇ or —C(O)OR₇; and R₇ is unsubstituted alkyl.

In some embodiments is a compound of Formula (V), wherein Y is

In some embodiments is a compound of Formula (V), wherein Y is

In some embodiments is a compound of Formula (V), wherein Y is

In some embodiments is a compound of Formula (V), wherein Y is

In some embodiments is a compound of Formula (V), wherein Y is

In some embodiments is a compound of Formula (V), wherein Y is

In some embodiments is a compound of Formula (V), wherein X is —O—. Insome embodiments is a compound of Formula (V), wherein X is —S—. In someembodiments is a compound of Formula (V), wherein X is —C(R₁)(R₂)—. Insome embodiments is a compound of Formula (V), wherein X is —C(R₁)(R₂)—and R₁ and R₂ is each independently hydrogen, substituted orunsubstituted alkyl, or substituted or unsubstituted aryl. In someembodiments is a compound of Formula (V), wherein X is —CH₂—. In someembodiments is a compound of Formula (V), wherein X is —CH(CH₃)—. Insome embodiments is a compound of Formula (V), wherein X is —C(CH₃)₂—.In some embodiments is a compound of Formula (V), wherein X is—C(R₁)(R₂)— and R₁ and R₂ together with the carbon atom to which theyare attached form a substituted or unsubstituted cycloalkyl group. Insome embodiments is a compound of Formula (V), wherein X is —N(R₅)—. Insome embodiments is a compound of Formula (V), wherein X is —N(R₅)— andR₅ is substituted or unsubstituted alkyl. In some embodiments is acompound of Formula (V), wherein X is —N(R₅)— and R₅ is unsubstitutedalkyl. In some embodiments is a compound of Formula (V), wherein X is—N(R₅)— and R₅ is substituted alkyl. In some embodiments is a compoundof Formula (V), wherein X is —N(R₅)— and R₅ is substituted orunsubstituted aryl. In some embodiments is a compound of Formula (V),wherein X is —N(R₅)— and R₅ is substituted phenyl. In some embodimentsis a compound of Formula (V), wherein X is —N(R₅)— and R₅ isunsubstituted phenyl. In some embodiments is a compound of Formula (V),wherein X is —NH—. In some embodiments is a compound of Formula (V),wherein X is —N(CH₃)—. In some embodiments is a compound of Formula (V),wherein X is —N(CH₂CH₃)—. In some embodiments is a compound of Formula(V), wherein X is —N(CH₂CH₂NH₂)—. In some embodiments is a compound ofFormula (V), wherein X is —N(CH₂CH₂NH(alkyl)-. In some embodiments is acompound of Formula (V), wherein X is —N(CH₂CH₂NH(CH₃))—. In a furtherembodiment of any of the aforementioned embodiments is a compound ofFormula (V), wherein Z is —CO₂H. In another embodiment of any of theaforementioned embodiments is a compound of Formula (V), wherein Z is—NR₃R₄. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (V), wherein Z is —NR₃R₄ and R₃ and R₄ are eachindependently hydrogen or substituted or unsubstituted alkyl. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (V), wherein Z is —NR₃R₄ and R₃ and R₄ are each independentlyhydrogen or methyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (V), wherein Z is —NR₃R₄ and R₃ andR₄ are each hydrogen. In another embodiment of any of the aforementionedembodiments is a compound of Formula (V), wherein Z is —NR₃R₄ and R₃ ishydrogen or R₄ is methyl. In another embodiment of any of theaforementioned embodiments is a compound of Formula (V), wherein n is 1.In another embodiment of any of the aforementioned embodiments is acompound of Formula (V), wherein n is 2. In another embodiment of any ofthe aforementioned embodiments is a compound of Formula (V), wherein nis 3. In another embodiment of any of the aforementioned embodiments isa compound of Formula (V), wherein n is 4. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (V), whereinn is 5. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (V), wherein n is 6. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (V),wherein n is 7. In another embodiment of any of the aforementionedembodiments is a compound of Formula (V), wherein n is 8. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (V), wherein n is 9. In another embodiment of any of theaforementioned embodiments is a compound of Formula (V), wherein n is10.

In another aspect, described herein is a compound having the structureof Formula (VI):

wherein:

Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolichydroxyl group is replaced by a covalent bond to—C(O)—X—(C(R₁)(R₂))_(n)—Z;

X is —C(R₁)(R₂)—, —O—, —N(R₅)— or —S—;

n is an integer from 1 to 10;

Z is —NR₃R₄;

R₅ is hydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and each R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,or substituted or unsubstituted acyl, or R₁ and R₂ together with thecarbon atom to which they are attached form a substituted cycloalkylgroup, or R₁ and R₂ together with the carbon atom to which they areattached form an unsubstituted cyclopropyl, cyclobutyl, cyclopentyl,cycloheptyl, or cyclooctyl or two R₁ or R₂ groups on adjacent carbonatoms, together with the carbon atoms to which they are attached, form asubstituted or unsubstituted cycloalkyl group, or R₁ and R₅ groups onadjacent atoms, together with the atoms to which they are attached, forma substituted or unsubstituted heterocycloalkyl group; and

R₃ and R₄ is each independently hydrogen, substituted or unsubstitutedalkyl, or substituted or unsubstituted aryl; or

a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof.

In some embodiments is a compound of Formula (VI), wherein Y is

In some embodiments is a compound of Formula (VI), wherein Y is

In some embodiments is a compound of Formula (VI), wherein Y is

In some embodiments is a compound of Formula (VI), wherein Y is

In some embodiments is a compound of Formula (VI), wherein Y is

In some embodiments is a compound of Formula (VI), wherein Y is

In some embodiments is a compound of Formula (VI), wherein X is —O—. Insome embodiments is a compound of Formula (VI), wherein X is —S—. Insome embodiments is a compound of Formula (VI), wherein X is—C(R₁)(R₂)—. In some embodiments is a compound of Formula (VI), whereinX is —C(R₁)(R₂)— and R₁ and R₂ is each independently hydrogen,substituted or unsubstituted alkyl, or substituted or unsubstitutedaryl. In some embodiments is a compound of Formula (VI), wherein X is—CH₂—. In some embodiments is a compound of Formula (VI), wherein X is—CH(CH₃)—. In some embodiments is a compound of Formula (VI), wherein Xis —C(CH₃)₂—. In some embodiments is a compound of Formula (VI), whereinX is —C(R₁)(R₂)— and R₁ and R₂ together with the carbon atom to whichthey are attached form a substituted cycloalkyl group. In someembodiments is a compound of Formula (VI), wherein X is —C(R₁)(R₂)— andR₁ and R₂ together with the carbon atom to which they are attached forman unsubstituted cyclopropyl group. In some embodiments is a compound ofFormula (VI), wherein X is —C(R₁)(R₂)— and R₁ and R₂ together with thecarbon atom to which they are attached form an unsubstituted cyclobutylgroup. In some embodiments is a compound of Formula (VI), wherein X is—C(R₁)(R₂)— and R₁ and R₂ together with the carbon atom to which theyare attached form an unsubstituted cyclopentyl group. In someembodiments is a compound of Formula (VI), wherein X is —C(R₁)(R₂)— andR₁ and R₂ together with the carbon atom to which they are attached forman unsubstituted cycloheptyl group. In some embodiments is a compound ofFormula (VI), wherein X is —C(R₁)(R₂)— and R₁ and R₂ together with thecarbon atom to which they are attached form an unsubstituted cyclooctylgroup. In some embodiments is a compound of Formula (VI), wherein X is—N(R₅)—. In some embodiments is a compound of Formula (VI), wherein X is—N(R₅)— and R₅ is substituted or unsubstituted alkyl. In someembodiments is a compound of Formula (VI), wherein X is —N(R₅)— and R₅is unsubstituted alkyl. In some embodiments is a compound of Formula(VI), wherein X is —N(R₅)— and R₅ is substituted alkyl. In someembodiments is a compound of Formula (VI), wherein X is —N(R₅)— and R₅is substituted or unsubstituted aryl. In some embodiments is a compoundof Formula (VI), wherein X is —N(R₅)— and R₅ is substituted phenyl. Insome embodiments is a compound of Formula (VI), wherein X is —N(R₅)— andR₅ is unsubstituted phenyl. In some embodiments is a compound of Formula(VI), wherein X is —NH—. In some embodiments is a compound of Formula(VI), wherein X is —N(CH₃)—. In some embodiments is a compound ofFormula (VI), wherein X is —N(CH₂CH₃)—. In some embodiments is acompound of Formula (VI), wherein X is —N(CH₂CH₂NH₂)—. In someembodiments is a compound of Formula (VI), wherein X is—N(CH₂CH₂NH(alkyl)-. In some embodiments is a compound of Formula (VI),wherein X is —N(CH₂CH₂NH(CH₃))—. In another embodiment of any of theaforementioned embodiments is a compound of Formula (VI), wherein Z is—NR₃R₄ and R₃ and R₄ are each independently hydrogen or substituted orunsubstituted alkyl. In another embodiment of any of the aforementionedembodiments is a compound of Formula (VI), wherein Z is —NR₃R₄ and R₃and R₄ are each independently hydrogen or methyl. In another embodimentof any of the aforementioned embodiments is a compound of Formula (VI),wherein Z is —NR₃R₄ and R₃ and R₄ are each hydrogen. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (VI), wherein Z is —NR₃R₄ and R₃ is hydrogen or R₄ is methyl. Inanother embodiment of any of the aforementioned embodiments is acompound of Formula (VI), wherein n is 1. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (VI), whereinn is 2. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (VI), wherein n is 3. In another embodiment ofany of the aforementioned embodiments is a compound of Formula (VI),wherein n is 4. In another embodiment of any of the aforementionedembodiments is a compound of Formula (VI), wherein n is 5. In anotherembodiment of any of the aforementioned embodiments is a compound ofFormula (VI), wherein n is 6. In another embodiment of any of theaforementioned embodiments is a compound of Formula (VI), wherein n is7. In another embodiment of any of the aforementioned embodiments is acompound of Formula (VI), wherein n is 8. In another embodiment of anyof the aforementioned embodiments is a compound of Formula (VI), whereinn is 9. In another embodiment of any of the aforementioned embodimentsis a compound of Formula (VI), wherein n is 10.

In another embodiment is a compound selected from:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof.

In another embodiment is a compound selected from:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof.

In another embodiment is a compound, or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate, or hydrate thereof, havingthe structure:

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich Corp., Fisher Scientific (Fisher Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compound as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein.

In some embodiments, the compounds described herein are prepared asoutlined in the following scheme.

In some embodiments, the compounds described herein are prepared asoutlined in the following scheme.

The compounds described herein may in me cases exist as diastereomers,enantiomers, or other stereoisomeric forms. The compounds presentedherein include all diastereomeric, enantiomeric, and epimeric forms aswell as the appropriate mixtures thereof. Separation of stereoisomersmay be performed by chromatography or by the forming diastereomeric andseparation by recrystallization, or chromatography, or any combinationthereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers,Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, hereinincorporated by reference for this disclosure). Stereoisomers may alsobe obtained by stereoselective synthesis.

In some situations, compounds may exist as tautomers. All tautomers areincluded within the formulas described herein.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).The compounds described herein may be in the form of pharmaceuticallyacceptable salts. As well, active metabolites of these compounds havingthe same type of activity are included in the scope of the presentdisclosure. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

The compounds of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or hydratethereof, described herein are prodrugs of TRPV1 agonists. A “prodrug”refers to an agent that is converted into the parent drug in vivo. Thecompounds of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or hydratethereof, described herein are directed to novel water-soluble prodrugsof TRPV1 agonists and their methods of synthesis and use. In addition tospecifically identified compounds, these derivatives are capable ofchemical reverting to the active parent compound when exposed tophysiological conditions. These derivatives have significantly higherhydrophilicity/water solubility than their parent drugs and are hencebetter able to be incorporated into commonly used aqueous formulations.Further described herein is a method of increasing the water solubilityof capsaicin, its analogs and other TRPV1 agonists, by modifying theparent molecule's chemical structure with hydrophilic moieties. In someembodiments described herein, the introduction of basic moieties capableof being protonated under acidic conditions increases the solubility ofa TRPV1 prodrug. In some embodiments described herein, the introductionof acidic moieties capable of increasing the overall hydrophiliccharacter increases the solubility of a TRPV1 prodrug. The prodrugsdescribed herein are designed such that the parent drug is releasedunder well-defined rates after its structural derivative has beendelivered to the body and/or is exposed to specific physiologicalconditions.

The compounds described herein may be labeled isotopically (e.g. with aradioisotope) or by other means, including, but not limited to, the useof chromophores or fluorescent moieties, bioluminescent labels,photoactivatable or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, forexample, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl, respectively.Certain isotopically-labeled compounds described herein, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Further, substitution with isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, such as, for example, increased in vivo half-lifeor reduced dosage requirements.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

In some embodiments, compounds described herein, such as compounds ofFormula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId),(IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb),(IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (Ille), (IIIee), (IIIf),(IIIff), (IV), (V), or (VI), are in various forms, including but notlimited to, amorphous forms, milled forms and nano-particulate forms. Inaddition, compounds described herein include crystalline forms, alsoknown as polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, melting points,density, hardness, crystal shape, optical properties, stability, andsolubility. Various factors such as the recrystallization solvent, rateof crystallization, and storage temperature may cause a single crystalform to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UV-VIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen to provide stable moieties and compounds.

Use of Protecting Groups (PG)

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

Protective groups can be removed by acid, base, reducing conditions(such as, for example, hydrogenolysis), and/or oxidative conditions.Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilylare acid labile and may be used to protect carboxy and hydroxy reactivemoieties in the presence of amino groups protected with Cbz groups,which are removable by hydrogenolysis, and Fmoc groups, which are baselabile. Carboxylic acid and hydroxy reactive moieties may be blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, which include conversion to alkyl esters, or they may be blockedwith oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups may be blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd⁰-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure).

Diseases, Disorders or Conditions

In another aspect is a method of treating pain in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or hydratethereof. In some embodiments is a method of treating pain in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb),(IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III),(IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd),(IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof, wherein the pain is associated with post-operativepain. In some embodiments is a method of treating pain in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb),(IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III),(IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd),(IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof, wherein the pain is associated with chronicpost-surgical pain. In some embodiments is a method of treating pain ina subject, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof, wherein the pain is associated withneuropathic pain. In some embodiments is a method of treating pain in asubject, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof, wherein the pain is associated withpostherpetic neuralgia. In some embodiments is a method of treating painin a subject, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof, wherein the pain is associated withdiabetic neuropathy. In some embodiments is a method of treating pain ina subject, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof, wherein the pain is associated withHIV-associated neuropathy. In some embodiments is a method of treatingpain in a subject, comprising administering to the subject atherapeutically effective amount of a compound of Formula (I), (II),(IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof, wherein the pain is associatedwith complex regional pain syndrome. In some embodiments is a method oftreating pain in a subject, comprising administering to the subject atherapeutically effective amount of a compound of Formula (I), (II),(IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof, wherein the pain is associatedwith cancer. In some embodiments is a method of treating pain in asubject, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof, wherein the pain is associated with cancerchemotherapy. In some embodiments is a method of treating pain in asubject, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof, wherein the pain is associated with nerveinjury. In some embodiments is a method of treating pain in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb),(IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III),(IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd),(IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof, wherein the pain is associated with vulvodynia. Insome embodiments is a method of treating pain in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or hydratethereof, wherein the pain is associated with trauma. In some embodimentsis a method of treating pain in a subject, comprising administering tothe subject a therapeutically effective amount of a compound of Formula(I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd),(IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb),(IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff),(IV), (V), or (VI), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or hydrate thereof, wherein thepain is associated with surgery. In some embodiments is a method oftreating pain in a subject, comprising administering to the subject atherapeutically effective amount of a compound of Formula (I), (II),(IIa), (IIaa), (IIb), (IIbb),)(IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof, wherein the pain is associatedwith chronic musculoskeletal pain. In some embodiments is a method oftreating pain in a subject, comprising administering to the subject atherapeutically effective amount of a compound of Formula (I), (II),(IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof, wherein the pain is associatedwith lower back pain. In some embodiments is a method of treating painin a subject, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof, wherein the pain is associated withosteoarthritis or rheumatoid arthritis. In some embodiments is a methodof treating pain in a subject, comprising administering to the subject atherapeutically effective amount of a compound of Formula (I), (II),(IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof, wherein the pain is associatedwith osteoarthritis arthritis. In some embodiments is a method oftreating pain in a subject, comprising administering to the subject atherapeutically effective amount of a compound of Formula (I), (II),(IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof, wherein the pain is associatedwith rheumatoid arthritis.

In some embodiments is a method of treating psoriasis, pruritis, itch,cancer, prostatic hypertrophy, wrinkles, sinusitis, rhinitis, alopecia,or hirsutism in a subject, comprising administering to the subject atherapeutically effective amount of a compound of Formula (I), (II),(IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof. In some embodiments is a methodof treating psoriasis in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of Formula (I),(II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (e),(IIe), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof. In some embodiments is a methodof treating pruritis in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of Formula (I),(II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof. In some embodiments is a methodof treating itch in a subject, comprising administering to the subject atherapeutically effective amount of a compound of Formula (I), (II),(IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof. In some embodiments is a methodof treating cancer in a subject, comprising administering to the subjecta therapeutically effective amount of a compound of Formula (I), (II),(IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof. In some embodiments is a methodof treating prostatic hypertrophy in a subject, comprising administeringto the subject a therapeutically effective amount of a compound ofFormula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId),(IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb),(IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf),(IIIff), (IV), (V), or (VI), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or hydrate thereof. In someembodiments is a method of treating sinusitis in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or hydratethereof. In some embodiments is a method of treating rhinitis in asubject, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof. In some embodiments is a method of treatingalopecia in a subject, comprising administering to the subject atherapeutically effective amount of a compound of Formula (I), (II),(IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof. In some embodiments is a methodof treating hirsutism in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of Formula (I),(II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or hydrate thereof.

In some embodiments is a method of treating pain in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb),(IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III),(IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd),(IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,or hydrate thereof, wherein the compound is administered locally. Insome embodiments is a method of treating pain in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or hydratethereof, wherein the compound is administered dermally. In someembodiments is a method of treating pain in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or hydratethereof, wherein the compound is administered transdermally. In someembodiments is a method of treating pain in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or hydratethereof, wherein the compound is administered systemically.

Certain Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood to which the claimedsubject matter belongs. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Allpatents, patent applications, publications and published nucleotide andamino acid sequences (e.g., sequences available in GenBank or otherdatabases) referred to herein are incorporated by reference. Wherereference is made to a URL or other such identifier or address, it isunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Definition of standard chemistry terms may be found in reference works,including but not limited to, Carey and Sundberg “ADVANCED ORGANICCHEMISTRY 4^(TH) ED.” Vols. A (2000) and B (2001), Plenum Press, NewYork. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology.

Unless specific definitions are provided, the nomenclature employed inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those recognized in thefield. Standard techniques can be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation, and delivery, andtreatment of patients. Standard techniques can be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection). Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures can be generallyperformed of conventional methods and as described in various generaland more specific references that are cited and discussed throughout thepresent specification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods, compounds, compositions describedherein.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

An “alkyl” group refers to an aliphatic hydrocarbon group, wherein ansp3-hybridized carbon of the alkyl residue is attached to the rest ofthe molecule by a single bond. The alkyl groups may or may not includeunits of unsaturation. The alkyl moiety may be a “saturated alkyl”group, which means that it does not contain any units of unsaturation(i.e. a carbon-carbon double bond or a carbon-carbon triple bond). Thealkyl group may also be an “unsaturated alkyl” moiety, which means thatit contains at least one unit of unsaturation. The alkyl moiety, whethersaturated or unsaturated, may be branched, straight chain, or cyclic.

The “alkyl” group may have 1 to 6 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 6” refers to each integer in thegiven range; e.g., “1 to 6 carbon atoms” means that the alkyl group mayconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₆ alkyl” or similar designations. By way of exampleonly, “C₁-C₆ alkyl” indicates that there are one to six carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl(allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted.Depending on the structure, an alkyl group can be a monoradical or adiradical (i.e., an alkylene group).

An “alkoxy” refers to a “—O-alkyl” group, where alkyl is as definedherein.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atoms—C(R)═CR₂, wherein R refers to the remaining portions of the alkenylgroup, which may be the same or different. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —CH═C(CH₃)₂ and—C(CH₃)═CHCH₃. The alkenyl moiety may be branched, straight chain, orcyclic (in which case, it would also be known as a “cycloalkenyl”group). Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can besubstituted or unsubstituted. Depending on the structure, an alkenylgroup can be a monoradical or a diradical (i.e., an alkenylene group).

The term “alkynyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a triple bond. That is, an alkynylgroup begins with the atoms —C≡C—R, wherein R refers to the remainingportions of the alkynyl group. Non-limiting examples of an alkynyl groupinclude —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃ and —C≡CCH₂CH₂CH₃. The “R” portion ofthe alkynyl moiety may be branched, straight chain, or cyclic. Analkynyl group can have 2 to 6 carbons. Alkynyl groups can be substitutedor unsubstituted. Depending on the structure, an alkynyl group can be amonoradical or a diradical (i.e., an alkynylene group).

“Amino” refers to a —NH₂ group.

The term “alkylamine” or “alkylamino” refers to the —N(alkyl)_(x)H_(y)group, where alkyl is as defined herein and x and y are selected fromthe group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, takentogether with the nitrogen to which they are attached, can optionallyform a cyclic ring system. “Dialkylamino” refers to a —N(alkyl)₂ group,where alkyl is as defined herein.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) andheteroaryl groups (e.g., pyridinyl, quinolinyl).

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, and naphthalenyl. Depending on thestructure, an aryl group can be a monoradical or a diradical (i.e., anarylene group).

As used herein, the term “acyl” refers to a group containing a carbonylmoiety wherein the group is bonded via the carbonyl carbon atom. Thecarbonyl carbon atom is also bonded to another carbon atom, which can bepart of an alkyl, aryl, aralkyl cycloalkyl, heterocycloalkyl, heteroarylgroup or the like.

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. Cycloalkyls may be saturated, or partiallyunsaturated. Cycloalkyls may be fused with an aromatic ring (in whichcase the cycloalkyl is bonded through a non-aromatic ring carbon atom).Cycloalkyl groups include groups having from 3 to 10 ring atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

and the like.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. Polycyclic heteroarylgroups may be fused or non-fused. Illustrative examples of heteroarylgroups include the following moieties:

and the like.

A “heterocycloalkyl” group or “heteroalicyclic” group refers to acycloalkyl group, wherein at least one skeletal ring atom is aheteroatom selected from nitrogen, oxygen and sulfur. The radicals maybe fused with an aryl or heteroaryl. Illustrative examples ofheterocycloalkyl groups, also referred to as non-aromatic heterocycles,include:

The term heteroalicyclic also includes all ring forms of thecarbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring).

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The term “haloalkyl” or “haloalkoxy” refers to an alkyl group or alkoxygroup that is substituted with one or more halogens. The halogens maythe same or they may be different. Non-limiting examples of haloalkylsinclude —CH₂Cl, —CF₃, —CHF₂, —CH₂CF₃, —CF₂CF₃, —CF(CH₃)₂, and the like.Non-limiting examples of haloalkoxys include —OCH₂Cl, —OCF₃, —OCHF₂,—OCH₂CF₃, —OCF₂CF₃, —OCF(CH₃)₂, and the like.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxygroups, respectively, that are substituted with one or more fluorineatoms. Non-limiting examples of fluoroalkyls include —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CF(CH₃)₃, and the like. Non-limitingexamples of fluoroalkoxy groups, include —OCF₃, —OCHF₂, —OCH₂F,—OCH₂CF₃, —OCF₂CF₃, —OCF₂CF₂CF₃, —OCF(CH₃)₂, and the like.

The term “heteroalkyl” refers to an alkyl radical where one or moreskeletal chain atoms is selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.The heteroatom(s) may be placed at any interior position of theheteroalkyl group. Examples include, but are not limited to, —CH₂—O—CH₃,—CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH₂—NH—OCH₃, —CH₂—O—Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. In addition, up to twoheteroatoms may be consecutive, such as, by way of example, —CH₂—NH—OCH₃and —CH₂—O—Si(CH₃)₃. Excluding the number of heteroatoms, a“heteroalkyl” may have from 1 to 6 carbon atoms.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon), and heterocycloalkyl.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, fluoroalkoxy, and amino, including mono- anddi-substituted amino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protectedderivatives thereof. In some embodiments, optional substituents areindependently selected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH,—CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl), —C(═O)N(alkyl)₂,—S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl, cycloalkyl,fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl,heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide,alkylsulfone, and arylsulfone. In some embodiments, optionalsubstituents are independently selected from halogen, —CN, —NH₂, —OH,—NH(CH₃), —N(CH₃)₂, —CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In someembodiments, substituted groups are substituted with one or two of thepreceding groups. In some embodiments, an optional substituent on analiphatic carbon atom (acyclic or cyclic, saturated or unsaturatedcarbon atoms, excluding aromatic carbon atoms) includes oxo (═O).

The methods and formulations described herein include the use ofcrystalline forms (also known as polymorphs), or pharmaceuticallyacceptable salts of compounds having the structure of Formula (I), (II),(IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI), as well as active metabolites of these compounds having thesame type of activity. In some situations, compounds may exist astautomers. All tautomers are included within the scope of the compoundspresented herein. In addition, the compounds described herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

The terms “kit” and “article of manufacture” are used as synonyms.

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying causes of symptoms, inhibiting the disease or condition,e.g., arresting the development of the disease or condition, relievingthe disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

As used herein, amelioration of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

The term “modulate,” as used herein, means to interact with a targetprotein either directly or indirectly so as to alter the activity of thetarget protein, including, by way of example only, to inhibit theactivity of the target, or to limit or reduce the activity of thetarget.

As used herein, the term “modulator” refers to a compound that alters anactivity of a target. For example, a modulator can cause an increase ordecrease in the magnitude of a certain activity of a target compared tothe magnitude of the activity in the absence of the modulator. Incertain embodiments, a modulator is an inhibitor, which decreases themagnitude of one or more activities of a target. In certain embodiments,an inhibitor completely prevents one or more activities of a target.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

By “pharmaceutically acceptable,” as used herein, refers a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that one activeingredient, e.g. a compound of Formula (I), (II), (IIa), (IIaa), (IIb),(IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff),(III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId),(IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI), and aco-agent, are both administered to a patient simultaneously in the formof a single entity or dosage. The term “non-fixed combination” meansthat one active ingredient, e.g. a compound of Formula (I), (II), (IIa),(IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee),(IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI),and a co-agent, are administered to a patient as separate entitieseither simultaneously, concurrently or sequentially with no specificintervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g. the administration of three or moreactive ingredients.

The term “pharmaceutical composition” refers to a mixture of a compoundof Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc),(IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa),(IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee),(IIIf), (IIIff), (IV), (V), or (VI) described herein with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. Multiple techniques of administering a compound exist inthe art including, but not limited to: intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary and topical administration.

The term “capsaicinoid or capsaisin analog” is meant to include anycompound that produces a selective, highly-localized destruction orincapacitation of C-fiber and/or A-delta-fiber in discrete localizedareas responsible for the initiation of pain for the purpose ofeliminating pain arising from that locus, while minimizing potentialadverse consequences of C-fiber and/or A-delta-fiber activation and/ordamage outside of the locus of pain such as (E)-capsaicin,resinifiatoxin, AM-404 (N-(4-Hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide), Anandamide, Arvanil,6′-Iodoresiniferatoxin, NADA (N-arachidonyldopamine), OLDA(N-oleoyldopamine), olvanil, and PPAHV (phorbol 12-phenylacetate13-acetate 20-homovanillate). Other suitable capsaicinoids for usedescribed herein include, but are not limited to, N-vanillylnonanamides,N-vanillylsulfonamides, N-vanillylureas, N-vanillylcarbamates,N-[(substituted phenyl)methyl]alkylamides, methylene substitutedN-[(substituted phenyl)methyl]alkanamides, N-[(substitutedphenyl)methyl]-cis-monosaturated alkenamides, N-[(substitutedphenyl)methyl]di-unsaturatedamides, 3-hydroxyacetanilide, hydroxyphenylacetamides, pseudocapsaicin, dihydrocapsaicin, nordihydrocapsaicin,homocapsaicin, homodihydrocapsaicin I, anandamide, piperine, zingerone,warburganal, polygodial, aframodial, cinnamodial, cinnamosmolide,cinnamolide, civainde, nonivamide, N-oleyl-homovanillamidia,isovelleral, scalaradial, ancistrodial, 3-acaridial, merulidial,scutigeral and any combinations or mixtures thereof.

The term “TRPV1 agonist”, as used herein, refers to a compound orcomposition that activates the the transient receptor potentialvanilloid 1 receptor (TRPV1). TRPV1 agonists include, but are notlimited to, capsaicin, dihydrocapsaicin, nordihydrocapsaicin,homodihydrocapsaicin, homocapsaicin, dihydrocapsaicin, nonivamide, andresiniferatoxin.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition that includes a compound of Formula (I), (II), (IIa),(IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee),(IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI)described herein required to provide a clinically significant decreasein disease symptoms. An appropriate “effective” amount in any individualcase may be determined using techniques, such as a dose escalationstudy.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Further information on metabolism may be obtainedfrom The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill(1996). Metabolites of the compounds disclosed herein can be identifiedeither by administration of compounds to a host and analysis of tissuesamples from the host, or by incubation of compounds with hepatic cellsin vitro and analysis of the resulting compounds.

“Bioavailability” refers to the percentage of the weight of the compounddisclosed herein (e.g. compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI)),that is delivered into the general circulation of the animal or humanbeing studied. The total exposure (AUC(0-∞)) of a drug when administeredintravenously is usually defined as 100% bioavailable (F %). “Oralbioavailability” refers to the extent to which a compound disclosedherein, is absorbed into the general circulation when the pharmaceuticalcomposition is taken orally as compared to intravenous injection.

“Blood plasma concentration” refers to the concentration of a compoundof Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc),(IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa),(IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee),(IIIf), (IIIff), (IV), (V), or (VI) disclosed herein, in the plasmacomponent of blood of a subject. It is understood that the plasmaconcentration of compounds described herein may vary significantlybetween subjects, due to variability with respect to metabolism and/orpossible interactions with other therapeutic agents. In accordance withone embodiment disclosed herein, the blood plasma concentration of thecompounds disclosed herein may vary from subject to subject. Likewise,values such as maximum plasma concentration (Cmax) or time to reachmaximum plasma concentration (Tmax), or total area under the plasmaconcentration time curve (AUC(0-∞)) may vary from subject to subject.Due to this variability, the amount necessary to constitute “atherapeutically effective amount” of a compound may vary from subject tosubject.

As used herein, “amelioration” refers to an improvement in a disease orcondition or at least a partial relief of symptoms associated with adisease or condition.

Pharmaceutical Compositions and Methods of Administration

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.Additional details about suitable excipients for pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins, 1999), herein incorporatedby reference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI) described herein, withother chemical components, such as carriers, stabilizers, diluents,dispersing agents, suspending agents, thickening agents, and/orexcipients. The pharmaceutical composition facilitates administration ofthe compound to an organism. In practicing the methods of treatment oruse provided herein, therapeutically effective amounts of compoundsdescribed herein are administered in a pharmaceutical composition to asubject having a disease, disorder, or condition to be treated. In someembodiments, the subject is a human. A therapeutically effective amountcan vary widely depending on the severity of the disease, the age andrelative health of the subject, the potency of the compound used andother factors. The compounds of Formula (I), (II), (IIa), (IIaa), (IIb),(IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff),(III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId),(IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI) can beused singly or in combination with one or more therapeutic agents ascomponents of mixtures (as in combination therapy).

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. Moreover, the pharmaceutical compositions described herein,which include a compound of Formula (I), (II), (IIa), (IIaa), (IIb),(IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff),(III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId),(IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI) describedherein, can be formulated into any suitable dosage form, including butnot limited to, aqueous oral dispersions, liquids, gels, syrups,elixirs, slurries, suspensions, aerosols, controlled releaseformulations, fast melt formulations, effervescent formulations,lyophilized formulations, tablets, powders, pills, dragees, capsules,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediaterelease and controlled release formulations.

One may administer the compounds and/or compositions in a local ratherthan systemic manner, for example, via injection of the compounddirectly into an organ or tissue, often in a depot preparation. Suchformulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Inaddition, the drug may be provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compound ofFormula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId),(IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb),(IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf),(IIIff), (IV), (V), or (VI) described herein, as an active ingredient infree-acid or free-base form, or in a pharmaceutically acceptable saltform. In addition, the methods and pharmaceutical compositions describedherein include the use of crystalline forms (also known as polymorphs),as well as active metabolites of these compounds having the same type ofactivity. In some situations, compounds may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. Additionally, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein (e.g. compounds of Formula (I), (II), (IIa), (IIaa), (IIb),(IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff),(III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId),(IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI)),optionally grinding the resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets, pills, or capsules. Suitable excipients include, for example,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder), acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In other embodiments,the pharmaceutical formulation is in the form of a powder. In stillother embodiments, the pharmaceutical formulation is in the form of atablet, including but not limited to, a fast-melt tablet. Additionally,pharmaceutical formulations of the compounds described herein may beadministered as a single capsule or in multiple capsule dosage form. Insome embodiments, the pharmaceutical formulation is administered in two,or three, or four, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofFormula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId),(IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb),(IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf),(IIIff), (IV), (V), or (VI) described herein, with one or morepharmaceutical excipients to form a bulk blend composition. Whenreferring to these bulk blend compositions as homogeneous, it is meantthat the particles of the compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (Ille), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI)described herein, are dispersed evenly throughout the composition sothat the composition may be subdivided into equally effective unitdosage forms, such as tablets, pills, and capsules. The individual unitdosages may also include film coatings, which disintegrate upon oralingestion or upon contact with diluent. These formulations can bemanufactured by conventional pharmacological techniques.

The pharmaceutical solid dosage forms described herein can include acompound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (Ille),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI) described herein, and oneor more pharmaceutically acceptable additives such as a compatiblecarrier, binder, filling agent, suspending agent, flavoring agent,sweetening agent, disintegrating agent, dispersing agent, surfactant,lubricant, colorant, diluent, solubilizer, moistening agent,plasticizer, stabilizer, penetration enhancer, wetting agent,anti-foaming agent, antioxidant, preservative, or one or morecombination thereof. In still other aspects, using standard coatingprocedures, such as those described in Remington's PharmaceuticalSciences, 20th Edition (2000), a film coating is provided around theformulation of the compound described herein. In one embodiment, some orall of the particles of the compound described herein are coated. Inanother embodiment, some or all of the particles of the compounddescribed herein are microencapsulated. In still another embodiment, theparticles of the compound described herein are not microencapsulated andare uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethyl celluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI)from a solid dosage form matrix as efficiently as possible,disintegrants are often used in the formulation, especially when thedosage forms are compressed with binder. Disintegrants help rupturingthe dosage form matrix by swelling or capillary action when moisture isabsorbed into the dosage form. Suitable disintegrants for use in thesolid dosage forms described herein include, but are not limited to,natural starch such as corn starch or potato starch, a pregelatinizedstarch such as National 1551 or Amijel®, or sodium starch glycolate suchas Promogel® or Explotab®, a cellulose such as a wood product,methylcrystalline cellulose, e.g., Avicel®, Avicel®PH101, Avicel® PH102,Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, andSolka-Floc®, methylcellulose, croscarmellose, or a cross-linkedcellulose, such as cross-linked sodium carboxymethylcellulose(Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linkedcroscarmellose, a cross-linked starch such as sodium starch glycolate, across-linked polymer such as crospovidone, a cross-linkedpolyvinylpyrrolidone, alginate such as alginic acid or a salt of alginicacid such as sodium alginate, a clay such as Veegum® HV (magnesiumaluminum silicate), a gum such as agar, guar, locust bean, Karaya,pectin, or tragacanth, sodium starch glycolate, bentonite, a naturalsponge, a surfactant, a resin such as a cation-exchange resin, citruspulp, sodium lauryl sulfate, sodium lauryl sulfate in combinationstarch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that canbe filled into soft or hard shell capsules and for tablet formulation,they ensure the tablet remaining intact after compression and helpassure blend uniformity prior to a compression or fill step. Materialssuitable for use as binders in the solid dosage forms described hereininclude, but are not limited to, carboxymethylcellulose, methylcellulose(e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USPPharmacoat-603, hydroxypropylmethylcellulose acetate stearate (AqoateHS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g.,Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystallinecellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesiumaluminum silicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. In some embodiments, formulators determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol can have a molecular weight of about 300 to about6000, or about 3350 to about 4000, or about 5400 to about 7000, vinylpyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

There is considerable overlap between additives used in the solid dosageforms described herein. Thus, the above-listed additives should be takenas merely exemplary, and not limiting, of the types of additives thatcan be included in solid dosage forms of the pharmaceutical compositionsdescribed herein.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of the compounds of Formula (I), (II), (IIa), (IIaa), (IIb),(IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff),(III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId),(IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI) describedherein from the formulation. In other embodiments, the film coating aidsin patient compliance (e.g., Opadry® coatings or sugar coating). Filmcoatings including Opadry® typically range from about 1% to about 3% ofthe tablet weight. In other embodiments, the compressed tablets includeone or more excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound described above, inside of a capsule. Insome embodiments, the formulations (non-aqueous suspensions andsolutions) are placed in a soft gelatin capsule. In other embodiments,the formulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule may beswallowed whole or the capsule may be opened and the contents sprinkledon food prior to eating. In some embodiments, the therapeutic dose issplit into multiple (e.g., two, three, or four) capsules. In someembodiments, the entire dose of the formulation is delivered in acapsule form.

In various embodiments, the particles of the compound of Formula (I),(II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe),(IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc),(IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V),or (VI) described herein and one or more excipients are dry blended andcompressed into a mass, such as a tablet, having a hardness sufficientto provide a pharmaceutical composition that substantially disintegrateswithin less than about 30 minutes, less than about 35 minutes, less thanabout 40 minutes, less than about 45 minutes, less than about 50minutes, less than about 55 minutes, or less than about 60 minutes,after oral administration, thereby releasing the formulation into thegastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with compounds described herein, which sufficientlyisolate the compound from other non-compatible excipients. Materialscompatible with compounds described herein are those that delay therelease of the compounds of Formula (I), (II), (IIa), (IIaa), (IIb),(IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff),(III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId),(IIIdd), (Ille), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI) in vivo.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including compounds described herein, include, butare not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel®or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such asE461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® S100, Eudragit® RD 100, Eudragit® E100, Eudragit® L12.5,Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols,e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,stearic acid, propylene glycol, oleic acid, and triacetin areincorporated into the microencapsulation material. In other embodiments,the microencapsulating material useful for delaying the release of thepharmaceutical compositions is from the USP or the National Formulary(NF). In yet other embodiments, the microencapsulation material isKlucel. In still other embodiments, the microencapsulation material ismethocel.

Microencapsulated compounds described herein may be formulated bymethods that include, e.g., spray drying processes, spinningdisk-solvent processes, hot melt processes, spray chilling methods,fluidized bed, electrostatic deposition, centrifugal extrusion,rotational suspension separation, polymerization at liquid-gas orsolid-gas interface, pressure extrusion, or spraying solvent extractionbath. In addition to these, several chemical techniques, e.g., complexcoacervation, solvent evaporation, polymer-polymer incompatibility,interfacial polymerization in liquid media, in situ polymerization,in-liquid drying, and desolvation in liquid media could also be used.Furthermore, other methods such as roller compaction,extrusion/spheronization, coacervation, or nanoparticle coating may alsobe used.

In still other embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When such salts are added to water, the acidsand the base react to liberate carbon dioxide gas, thereby causing“effervescence.” Examples of effervescent salts include, e.g., thefollowing ingredients: sodium bicarbonate or a mixture of sodiumbicarbonate and sodium carbonate, citric acid and/or tartaric acid. Anyacid-base combination that results in the liberation of carbon dioxidecan be used in place of the combination of sodium bicarbonate and citricand tartaric acids, as long as the ingredients were suitable forpharmaceutical use and result in a pH of about 6.0 or higher.

In other embodiments, the formulations described herein, which include acompound described herein, are solid dispersions. Methods of producingsuch solid dispersions include, but are not limited to, for example,U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269,and U.S. patent publication no. 2004/0013734. In still otherembodiments, the formulations described herein are solid solutions.Solid solutions incorporate a substance together with the active agentand other excipients such that heating the mixture results indissolution of the drug and the resulting composition is then cooled toprovide a solid blend which can be further formulated or directly addedto a capsule or compressed into a tablet. Methods of producing suchsolid solutions include, but are not limited to, for example, U.S. Pat.Nos. 4,151,273, 5,281,420, and 6,083,518.

The pharmaceutical solid oral dosage forms including formulationsdescribed herein, which include a compounds described herein, can befurther formulated to provide a controlled release of the compound ofFormula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId),(IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb),(IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf),(IIIff), (IV), (V), or (VI). Controlled release refers to the release ofthe compounds described herein from a dosage form in which it isincorporated according to a desired profile over an extended period oftime. Controlled release profiles include, for example, sustainedrelease, prolonged release, pulsatile release, and delayed releaseprofiles. In contrast to immediate release compositions, controlledrelease compositions allow delivery of an agent to a subject over anextended period of time according to a predetermined profile. Suchrelease rates can provide therapeutically effective levels of agent foran extended period of time and thereby provide a longer period ofpharmacologic response while minimizing side effects as compared toconventional rapid release dosage forms. Such longer periods of responseprovide for many inherent benefits that are not achieved with thecorresponding short acting, immediate release preparations.

In some embodiments, the solid dosage forms described herein can beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. The enteric coated dosage formmay be a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

The term “rapid release” or “delayed release” as used herein refers tothe delivery so that the release can be accomplished at some generallypredictable rate. In some embodiments the method for delay of release iseither the tuning of the intramolecular cyclization-release reaction orvia the addition of buffers to modify the initiation of theintramolecular cyclization-release reaction.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants(e.g., carnuba wax or PEG) may be added to the coatings besidesplasticizers to solubilize or disperse the coating material, and toimprove coating performance and the coated product.

In other embodiments, the formulations described herein, which include acompound of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI) described herein, aredelivered using a pulsatile dosage form. A pulsatile dosage form iscapable of providing one or more immediate release pulses atpredetermined time points after a controlled lag time or at specificsites. Pulsatile dosage forms may be administered using a variety ofpulsatile formulations including, but are not limited to, thosedescribed in U.S. Pat. Nos. 5,011,692; 5,017,381; 5,229,135; 5,840,329;4,871,549; 5,260,068; 5,260,069; 5,508,040; 5,567,441 and 5,837,284.

Many other types of controlled release systems are suitable for use withthe formulations described herein. Examples of such delivery systemsinclude, e.g., polymer-based systems, such as polylactic andpolyglycolic acid, polyanhydrides and polycaprolactone; porous matrices,nonpolymer-based systems that are lipids, including sterols, such ascholesterol, cholesterol esters and fatty acids, or neutral fats, suchas mono-, di- and triglycerides; hydrogel release systems; silasticsystems; peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using conventional binders and the like. See, e.g.,Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214(1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2ndEd., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725; 4,624,848; 4,968,509;5,461,140; 5,456,923; 5,516,527; 5,622,721; 5,686,105; 5,700,410;5,977,175; 6,465,014; and 6,932,983.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of the compounds described herein, e.g. compounds ofFormula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId),(IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb),(IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf),(IIIff), (IV), (V), or (VI), and at least one dispersing agent orsuspending agent for oral administration to a subject. The formulationsmay be a powder and/or granules for suspension, and upon admixture withwater, a substantially uniform suspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

The pharmaceutical compositions described herein may include sweeteningagents such as, but not limited to, acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tuttifruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol,or any combination of these flavoring ingredients, e.g., anise-menthol,cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint,honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream,vanilla-mint, and mixtures thereof.

In some embodiments, the pharmaceutical formulations described hereincan be self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase can beadded just prior to administration, which ensures stability of anunstable or hydrophobic active ingredient. Thus, the SEDDS provides aneffective delivery system for oral and parenteral delivery ofhydrophobic active ingredients. SEDDS may provide improvements in thebioavailability of hydrophobic active ingredients. Methods of producingself-emulsifying dosage forms include, but are not limited to, forexample, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

There is overlap between the above-listed additives used in the aqueousdispersions or suspensions described herein, since a given additive isoften classified differently by different practitioners in the field, oris commonly used for any of several different functions. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in formulationsdescribed herein.

Potential excipients for intranasal formulations include, for example,U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Formulationssolutions in saline, employing benzyl alcohol or other suitablepreservatives, fluorocarbons, and/or other solubilizing or dispersingagents. See, for example, Ansel, H. C. et al., Pharmaceutical DosageForms and Drug Delivery Systems, Sixth Ed. (1995). Preferably thesecompositions and formulations are prepared with suitable nontoxicpharmaceutically acceptable ingredients. The choice of suitable carriersis highly dependent upon the exact nature of the nasal dosage formdesired, e.g., solutions, suspensions, ointments, or gels. Nasal dosageforms generally contain large amounts of water in addition to the activeingredient. Minor amounts of other ingredients such as pH adjusters,emulsifiers or dispersing agents, preservatives, surfactants, gellingagents, or buffering and other stabilizing and solubilizing agents mayalso be present. Preferably, the nasal dosage form should be isotonicwith nasal secretions.

For administration by inhalation, the compounds described herein may bein a form as an aerosol, a mist or a powder. Pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the compound described herein and a suitable powder base such aslactose or starch.

Buccal formulations that include compounds described herein may beadministered using a variety of formulations which include, but are notlimited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and5,739,136. In addition, the buccal dosage forms described herein canfurther include a bioerodible (hydrolysable) polymeric carrier that alsoserves to adhere the dosage form to the buccal mucosa. The buccal dosageform is fabricated so as to erode gradually over a predetermined timeperiod, wherein the delivery of the compound is provided essentiallythroughout. Buccal drug delivery avoids the disadvantages encounteredwith oral drug administration, e.g., slow absorption, degradation of theactive agent by fluids present in the gastrointestinal tract and/orfirst-pass inactivation in the liver. With regard to the bioerodible(hydrolysable) polymeric carrier, virtually any such carrier can beused, so long as the desired drug release profile is not compromised,and the carrier is compatible with the compounds described herein, andany other components that may be present in the buccal dosage unit.Generally, the polymeric carrier comprises hydrophilic (water-solubleand water-swellable) polymers that adhere to the wet surface of thebuccal mucosa. Examples of polymeric carriers useful herein includeacrylic acid polymers and co, e.g., those known as “carbomers”(Carbopol®, which may be obtained from B.F. Goodrich, is one suchpolymer). Other components may also be incorporated into the buccaldosage forms described herein include, but are not limited to,disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. For buccal or sublingual administration,the compositions may take the form of tablets, lozenges, or gelsformulated in a conventional manner.

Transdermal formulations described herein may be administered using avariety of devices including but not limited to, U.S. Pat. Nos.3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097,3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894,4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299,4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983,6,929,801 and 6,946,144.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiment, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound ofFormula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId),(IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb),(IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf),(IIIff), (IV), (V), or (VI); (2) a penetration enhancer; and (3) anaqueous adjuvant. In addition, transdermal formulations can includeadditional components such as, but not limited to, gelling agents,creams and ointment bases, and the like. In some embodiments, thetransdermal formulation can further include a woven or non-woven backingmaterial to enhance absorption and prevent the removal of thetransdermal formulation from the skin. In other embodiments, thetransdermal formulations described herein can maintain a saturated orsupersaturated state to promote diffusion into the skin.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds described herein. Therate of absorption can be slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Formulations suitable for intramuscular, subcutaneous, or intravenousinjection may include physiologically acceptable sterile aqueous ornon-aqueous solutions, dispersions, suspensions or emulsions, andsterile powders for reconstitution into sterile injectable solutions ordispersions. Examples of suitable aqueous and non-aqueous carriers,diluents, solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally recognized in the field. For other parenteral injections,appropriate formulations may include aqueous or nonaqueous solutions,preferably with physiologically compatible buffers or excipients. Suchexcipients are generally recognized in the field.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and are formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,medicated sticks, balms, creams or ointments. Such pharmaceuticalcompounds can contain solubilizers, stabilizers, tonicity enhancingagents, buffers and preservatives.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Generally, an agent, such as a compound of Formula (I), (II), (IIa),(IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee),(IIf), (IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI) isadministered in an amount effective for amelioration of, or preventionof the development of symptoms of, the disease or disorder (i.e., atherapeutically effective amount). Thus, a therapeutically effectiveamount can be an amount that is capable of at least partially preventingor reversing a disease or disorder. The dose required to obtain aneffective amount may vary depending on the agent, formulation, diseaseor disorder, and individual to whom the agent is administered.

Determination of effective amounts may also involve in vitro assays inwhich varying doses of agent are administered to cells in culture andthe concentration of agent effective for ameliorating some or allsymptoms is determined in order to calculate the concentration requiredin vivo. Effective amounts may also be based in in vivo animal studies.

An agent can be administered prior to, concurrently with and subsequentto the appearance of symptoms of a disease or disorder. In someembodiments, an agent is administered to a subject with a family historyof the disease or disorder, or who has a phenotype that may indicate apredisposition to a disease or disorder, or who has a genotype whichpredisposes the subject to the disease or disorder.

The particular delivery system used can depend on a number of factors,including, for example, the intended target and the route ofadministration, e.g., local or systemic. Targets for delivery can bespecific cells which are causing or contributing to a disease ordisorder. For example, a target cell can be resident or infiltratingcells in the nervous system contributing to a neurological,neurodegenerative or demyelinating disease or disorder. Administrationof an agent can be directed to one or more cell types or subsets of acell type by methods recognized in the field. For example, an agent canbe coupled to an antibody, ligand to a cell surface receptor or a toxin,or can be contained in a particle that is selectively internalized intocells, e.g., liposomes or a virus in which the viral receptor bindsspecifically to a certain cell type, or a viral particle lacking theviral nucleic acid, or can be administered locally.

Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the modulation of TRPV1, or for the treatment ofdiseases or conditions that would benefit, at least in part, frommodulation of TRPV1. In addition, a method for treating any of thediseases or conditions described herein in a subject in need of suchtreatment, involves administration of pharmaceutical compositionscontaining at least one compound described herein, or a pharmaceuticallyacceptable salt, or pharmaceutically acceptable solvate or hydratethereof, in therapeutically effective amounts to said subject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

Upon the doctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

Upon the doctor's discretion the administration of the compounds may begiven continuously; alternatively, the dose of drug being administeredmay be temporarily reduced or temporarily suspended for a certain lengthof time (i.e., a “drug holiday”). The length of the drug holiday canvary between 2 days and 1 year, including by way of example only, 2days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days,20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350days, or 365 days. The dose reduction during a drug holiday may be fromabout 10% to about 100%, including, by way of example only, about 10%,about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, or about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determined in amanner recognized in the field according to the particular circumstancessurrounding the case, including, e.g., the specific agent beingadministered, the route of administration, the condition being treated,and the subject or host being treated. In general, however, dosesemployed for adult human treatment will typically be in the range ofabout 0.001 mg per day to about 5000 mg per day, in some embodiments,about 1 mg per day to about 1500 mg per day. The desired dose mayconveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds described hereindescribed herein are from about 0.001 mg/kg to about 30 mg/kg. In oneembodiment, the daily dosages are from about 0.01 mg/kg to about 10mg/kg. An indicated daily dosage in the larger mammal, including, butnot limited to, humans, is in the range from about 0.1 mg to about 1000mg, conveniently administered in a single dose or in divided doses,including, but not limited to, up to four times a day or in extendedrelease form. Suitable unit dosage forms for oral administration includefrom about 1 to about 500 mg active ingredient. In one embodiment, theunit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about500 mg. The foregoing ranges are merely suggestive, as the number ofvariables in regard to an individual treatment regime is large, andconsiderable excursions from these recommended values are not uncommon.Such dosages may be altered depending on a number of variables, notlimited to the activity of the compound used, the disease or conditionto be treated, the mode of administration, the requirements of theindividual subject, the severity of the disease or condition beingtreated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Treatments

The compounds of Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc),(IIcc), (IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa),(IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe),(IIIee), (IIIf), (IIIff), (IV), (V), or (VI), and compositions thereof,may also be used in combination with other therapeutic agents that areselected for their therapeutic value for the condition to be treated. Ingeneral, the compositions described herein and, in embodiments wherecombinational therapy is employed, other agents do not have to beadministered in the same pharmaceutical composition, and may, because ofdifferent physical and chemical characteristics, have to be administeredby different routes. The determination of the mode of administration andthe advisability of administration, where possible, in the samepharmaceutical composition, is well within the knowledge of theclinician. The initial administration can be made according toestablished protocols recognized in the field, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the clinician.

In certain instances, it may be appropriate to administer at least onecompound described herein in combination with another therapeutic agent.By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds herein, such as a compoundof Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc),(IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa),(IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee),(IIIf), (IIIff), (IV), (V), or (VI), is nausea, then it may beappropriate to administer an anti-nausea agent in combination with theinitial therapeutic agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may haveminimal therapeutic benefit, but in combination with another therapeuticagent, the overall therapeutic benefit to the patient is enhanced). Or,by way of example only, the benefit experienced by a patient may beincreased by administering one of the compounds described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

In certain instances, the combination with another therapeutic agent iswith a local anesthetic agent. As used herein, the term “localanesthetic” means a drug which provides local numbness or pain relief.Exemplary exampels of local anesthetic agents which can be used incombination with the present invention include: bupivacaine,levobupivaine, ropivacaine, dibucaine, procaine, chloroprocaine,priolocaine, mepivacaine, etidocaine, tetracaine and lidocaine.

In certain instances, the combination with another therapeutic agent iswith a vasoconstrictor. Vasoconstrictors are useful are those actinglocally to restrict blood flow, and thereby retain the injected drugs inthe region in which they are administered. This has the effect ofsubstantially decreasing systemic toxicity. Preferred vasoconstrictorsare those acting on alpha adrenergic receptors, such as epinephrine andphenylepinephrine.

In certain instances, the combination with another therapeutic agent iswith a glucocorticoid. The glucocorticoid is selected from the groupconsisting of dexamethasone, cortisone, hydrocortisone, prednisone,beclomethasone, betamethasone, flunisolide, methyl prednisone, paramethasone, prednisolone, triamcinolome, alclometasone, amcinonide,clobetasol, fludrocortisone, diflurosone diacetate, fluocinoloneacetonide, fluoromethalone, flurandrenolide, halcinonide, medrysone,mometasone, and pharmaceutically acceptable salts and mixtures thereof.

In some embodiments, a compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof, is used in combination with a localanethetic.

In some embodiments, a compound of Formula (I), (II), (IIa), (IIaa),(IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf),(IIff), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc),(IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V), or (VI),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof, is used in combination with a non-opiodanalgesic.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds may beadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compounds used. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the physician afterevaluation of the disease being treated and the condition of thepatient.

Therapeutically-effective dosages can vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically-effective dosages of drugs and other agents for use incombination treatment regimens are described in the literature. Forexample, the use of metronomic dosing, i.e., providing more frequent,lower doses in order to minimize toxic side effects, has been describedextensively in the literature. Combination treatment further includesperiodic treatments that start and stop at various times to assist withthe clinical management of the patient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc),(IId), (IIdd), (IIe), (IIee), (IIf), (IIff), (III), (IIIa), (IIIaa),(IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee),(IIIf), (IIIff), (IV), (V), or (VI) described herein) may beadministered in any order or even simultaneously. If simultaneously, themultiple therapeutic agents may be provided in a single, unified form,or in multiple forms (by way of example only, either as a singleinjection or as two separate injections). One of the therapeutic agentsmay be given in multiple doses, or both may be given as multiple doses.If not simultaneous, the timing between the multiple doses may vary frommore than zero weeks to less than four weeks. In addition, thecombination methods, compositions and formulations are not to be limitedto the use of only two agents; the use of multiple therapeuticcombinations are also envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder or condition from which the subject suffers, as well as theage, weight, sex, diet, and medical condition of the subject. Thus, thedosage regimen actually employed can vary widely and therefore candeviate from the dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The compounds and compositionscan be administered to a subject during or as soon as possible after theonset of the symptoms. The administration of the compounds can beinitiated within the first 48 hours of the onset of the symptoms,preferably within the first 48 hours of the onset of the symptoms, morepreferably within the first 6 hours of the onset of the symptoms, andmost preferably within 3 hours of the onset of the symptoms. The initialadministration can be via any route practical, such as, for example, anintravenous injection, a bolus injection, infusion over about 5 minutesto about 5 hours, a pill, a capsule, transdermal patch, buccal delivery,and the like, or combination thereof. A compound is preferablyadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease, such as, for example, from 1 day toabout 3 months. The length of treatment can vary for each subject, andthe length can be determined using the known criteria. For example, thecompound or a formulation containing the compound can be administeredfor at least 2 weeks, preferably about 1 month to about 5 years.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits can includea carrier, package, or container that is compartmentalized to receiveone or more containers such as vials, tubes, and the like, each of thecontainer(s) including one of the separate elements to be used in amethod described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers can be formedfrom a variety of materials such as glass or plastic.

For example, the container(s) can include one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically may include one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein. The starting materialsand reagents used for the synthesis of the compounds described hereinmay be synthesized or can be obtained from commercial sources, such as,but not limited to, Sigma-Aldrich Corp., Acros Organics, Fluka, andFisher Scientific.

Synthetic Examples Example 1: Synthesis of(E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl(2-aminoethyl)(methyl)carbamate (1)

Preparation of Compound A-1

Capsaisin (200 mg, 0.65 mmol, 1.0 eq) was dissolved in DCM (10 mL),followed by the addition of 4-nitrophenylchloroformate (138 mg, 0.68mmol, 1.05 eq) and DIPEA (346 mL, 1.95 mmol, 3.0 eq). The reaction wasallowed to stir at room temperature for 4 h. To the reaction was thenadded HOAt (97 mg, 0.715 mmol, 1.1 eq) and tert-butyl(2-(methylamino)ethyl)carbamate (135 mg, 0.78 mmol, 1.2 eq). Thereaction was allowed to stir over (18 h) at room temperature. Next, thereaction was washed with 1N HCl (2×15 mL), saturated aq. NaHCO₃ (5×15mL) and finally saturated brine (15 mL). The organic layer was removed,dried over MgSO4, filtered and condensed under vacuum to afford A-1. Thematerial was used without further purification.

Preparation of Compound 1

To crude A-1 (from reaction mixture obtained above), was added DCM (3mL) and trifluoroacetic acid (1 mL). The reaction mixture was allowed tostir for 1 h at room temperature. Next, the reaction was condensed anddissolved in 1:1 HOAc:H₂O (10 mL). The crude mixture was purified bypreparative reverse phase HPLC (Agilent Prep C-18 column, mobile phaseA: 100% water, 0.1% TFA; mobile phase B: 100% ACN, 0.1% TFA; gradientelution 20% to 70% B over 20 min) to afford the TFA salt of Compound 1(188.1 mg, 0.36 mmol, 55.6% yield over two steps) as a white solid.LC-MS [M+H] 406.6 (Chemical Formula: C₂₂H₃₅N₃O₄+H, calc: 406.3).

Example 2: Synthesis of(E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenylmethyl(2-(methylamino)ethyl)carbamate (2)

The preparation of Compound 2 followed the synthetic methods of Example1, except for the substitution of tert-butyl(2-(methylamino)ethyl)carbamate with tert-butylmethyl(2-(methylamino)ethyl)carbamate. This method provided the TFA saltof the title compound as a white solid (192.7 mg, 0.36 mmol, 55.4%yield). LC-MS [M+H] 420.7 (Chemical Formula: C₂₃H₃₇N₃O₄+H, calc: 420.2).

Example 3: Synthesis of(E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl2-(aminomethyl)piperidine-1-carboxylate (3)

The preparation of Compound 3 followed the synthetic methods of Example1, except for the substitution of tert-butyl(2-(methylamino)ethyl)carbamate with tert-butyl(piperidin-2-ylmethyl)carbamate. This method provided the TFA salt ofthe title compound as a white solid (222.4 mg, 0.39 mmol, 61.1% yield).LC-MS [M+H] 446.7 (Chemical Formula: C₂₅H₃₉N₃O₄+H, calc: 446.3).

Example 4: Synthesis of(E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl2-(aminomethyl)pyrrolidine-1-carboxylate (4)

The preparation of Compound 4 followed the synthetic methods of Example1, except for the substitution of tert-butyl (2-(methylamino)ethyl)carbamate with tert-butyl (pyrrolidin-2-ylmethyl)carbamate.This method provided the TFA salt of the title compound as a white solid(202.1 mg, 0.37 mmol, 57.0% yield). LC-MS [M+H] 432.7 (Chemical Formula:C₂₄H₃₇N₃O₄+H, calc: 432.2).

Example 5: Synthesis of(E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenylbis(2-aminoethyl)carbamate (5)

The preparation of Compound 5 followed the synthetic methods of Example1, except for the substitution of tert-butyl (2-(methylamino)ethyl)carbamate with di-tert-butyl(azanediylbis(ethane-2,1-diyl))dicarbamate. This method provided the TFAsalt of the title compound as a white solid (217.0 mg, 0.33 mmol, 50.4%yield). LC-MS [M+H] 435.7 (Chemical Formula: C₂₃H₃₈N₃O₄+H, calc: 435.2).

Example 6: Synthesis of(E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl(3-aminopropyl)(methyl)carbamate (6)

The preparation of Compound 6 followed the synthetic methods of Example1, except for the substitution of tert-butyl (2-(methylamino)ethyl)carbamate with tert-butyl (3-(methylamino)propyl)carbamate.This method provided the TFA salt of the title compound as a white solid(149.6 mg, 0.28 mmol, 43.0% yield). LC-MS [M+H] 420.7 (Chemical Formula:C₂₃H₃₇N₃O₄+H, calc: 420.5).

Example 7: Synthesis of(E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl2-((methylamino)methyl)piperidine-1-carboxylate (7)

The preparation of Compound 7 followed the synthetic methods of Example1, except for the substitution of tert-butyl (2-(methylamino)ethyl)carbamate with tert-butylmethyl(piperidin-2-ylmethyl)carbamate. This method provided the TFA saltof the title compound as a white solid (183.2 mg, 0.32 mmol, 49.2%yield). LC-MS [M+H] 460.7 (Chemical Formula: C₂₃H₃₇N₃O₄+H, calc: 460.3).

Example 8: Synthesis of(E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenylpiperazine-1-carboxylate (8)

The preparation of Compound 8 followed the synthetic methods of Example1, except for the substitution of tert-butyl(2-(methylamino)ethyl)carbamate with tert-butylpiperazine-1-carboxylate. This method provided the TFA salt of the titlecompound as a white solid (186.4 mg, 0.35 mmol, 53.9% yield). LC-MS[M+H] 418.4 (Chemical Formula: C₂₃H₃₇N₃O₄+H, calc: 418.3).

Example 9: Synthesis of(E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenylpiperazine-1-carboxylate (9)

Compound 9 is prepared following the synthetic methods of Example 1,except for the substitution of tert-butyl(2-(methylamino)ethyl)carbamate with tert-butylmethyl((4-methylpiperazin-2-yl)methyl)carbamate.

In Vitro Assays

Example 10: Solubility Assay

In order to determine the aqueous solubility of the compounds describedherein, the HCl salts of the following compounds were incubated ateither 50 or 100 mg/mL in DI water followed by shaking for 24 hours. Thesolutions were then centrifuged and visually inspected for insolublematerial. In all cases, no insoluble material was observed.

Solubility Example (Compound) Structure Solubility in DI water^(a) 1(Compound 3)

>100 mg/mL 2 (Compound 5)

>100 mg/mL 3 (Compound 7)

 >50 mg/mL ^(a)Supernatant was diluted for quantification with a 3-pointcalibration curve.

In comparison to the aqueous solubility of capsaicin in water (˜0.064mg/mL), the hydrogen chloride salts of these compounds present adramatic increase in water solubility. Generally speaking, thisrepresents a greater than 1560-fold (examples 1 & 2) and 780-fold(example 3) increase in aquesous solubility from the parent compound,capsaicin.

These results represent a substantial advantage of using the compoundsdescribed herein over capsaicin when aqueous solutions are preferred fordelivery. For example, significantly more material of the compoundsdescribed herein (vs. capsaicin) can be delivered per unit volume ofaqueous solution without the use of additional solubilizing agents.

Example 11: In Vitro (pH Stability) Assay

The release of parent drug (e.g. capsaicin) from the compounds describedherein was demonstrated by the synthesis and stability testing ofseveral compounds. These compounds are examples of pH activated prodrugswhereby upon exposure to a specific pH, the half-life of theintramolecular cyclization-release reaction is determined. As previouslydescribed, the intramolecular cyclization-release reaction results inthe concomitant formation of a cyclic urea with the release of theparent drug.

Compounds were incubated in the buffer/biological media indicated (TRIS®obtained from Sigma-Aldrich, St. Louis, Mo., USA, Catalog No. T1503).The reactions were conducted at either room temperature or 37° C.Samples were collected at specific time points, transferred into a 0.1%HCl solution to stop the cyclization-release reaction and analyzed byHPLC for formation of capsaicin and consumption of starting compound.

Intramolecular Cyclization- Example Compound Release Half-life(T_(1/2))^(a,b) 1

~24.1 h^(a) 2

~3.2 h^(a) 3

~31.6 min^(a) ~12.9 min^(b) 4

~12.3 d^(a) 5

~71.1 min^(a) ~24.7 min^(b) 6

~30.8 d^(a) 7

~4.4 min^(a) ~3.1 min^(b) 8

N/A^(a) Conditions: ^(a) pH = ~7.4 (0.3M aqueous tris buffer), 20° C.;^(b) pH = ~7.4 (1.0M aqueous tris buffer), 37° C.; N/A: Example 8 didnot show any measureable conversion to capsaicin over 2 weeks.

Although there were structural similarities between the compoundstested, the set of compounds tested demonstrated a wide range ofcyclization rates. The intramolecular cyclization-release half-liferesults ranged from minutes (examples 3, 5 and 7) to days (examples 4and 6). These results present a useful set of compounds for rapid ordelayed delivery of the parent drug.

Additional common ingredients/formulations which may be used in buffersfor the testing of the cyclization-release of the compounds describedherein include but are not limited to:N-(2-Acetamido)-2-aminoethanesulfonic acid, N-(2-Acetamido)iminodiaceticacid, 2-Amino-2-methyl-1,3-propanediol, salts of bicarbonate,N,N-Bis(2-hydroxyethyl)glycine,2-Bis(2-hydroxyethyl)amino-2-(hydroxymethyl)-1,3-propanediol,3-(Cyclohexylamino)-1-propanesulfonic acid,2-(Cyclohexylamino)ethanesulfonic acid, salts of carbonate, salts ofcitrate, 4-(2-Hydroxyethyl)-1-piperazinepropanesulfonic acid, salts ofglycine, salts of Glycyl-glycine,4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid,4-Morpholineethanesulfonic acid, 4-Morpholinepropanesulfonic acid,1,4-Piperazinediethanesulfonic acid, salts of phosphate, salts oftartrate, 2-[(2-Hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonicacid, Tris(2-hydroxyethyl)amine, and salts of EDTA.

Example 12: In Vitro Binding Assay

Due to the intrinsic pH instability of the compounds described herein,testing of Compounds 1-7 in a half maximal inhibitory concentration(IC₅₀) assay would be compromised due to the formation the parent drug(capsaicin) under the assay conditions (pH=−7-8). However, compound 8,which contains a chemically releated amino-carbamate moiety but ischemically

incapable of an intramolecular cyclization-release reaction,demonstrated minimal binding to TRPV receptor with an IC50>100 uM (23%inhibition @ 100 uM). Eurofins, Panlabs/Cerep assay name: Vanilloid,Catalog Number: 286810; concurrent control: Resiniferatoxin=0.16 nM,historical controls: Capsaicin=3.1 μM, Resiniferatoxin=0.46 nM. Sincecompound 8 is essentially devoid of activity at the vanilloid receptorand by definition would not be considered a capsaicinoid, it followsthat the compounds described herein (for example compounds 1-7) woulddemonstrate similar binding properties and would not be classified ascapsaicinoids either.

Additionally, structure-relation-activity (SAR) data from multiplereferences has demonstrated that substitution of the phenolic positionof capsaisin and resinifiatoxin generates compounds with greatlydimished activity for the TRPV1 receptor (Huang, et. al. CurrentMedicinal Chemistry, 2013, 20, 2661-2672).

Example 13: Pharmacokinetic Assay—Plasma Timecourse of Test CompoundsFollowing IM Administration to Rat

IM dosing: The test compounds are dissolved in saline and dosed viaintramuscular injection into male Sprague-Dawley rats. Capsaisin is usedas a positive control and the test compounds are dosed as the HCl salts.Test compounds are dosed as mg/kg body weight and are molar corrected tomatch the amount of capsaicin dosed. At specific time points (0.5 h, 1h, 2 h, 4 h, 8 h, 12 h, 24 h, 36 h, 72 h), blood samples are drawn,quenched into ACN (containing 0.5% formic acid), centrifuged at 14000rpm @ rt and stored at −80° C., until analysis. Samples are quantifiedvia LC/MS/MS. Plasma concentration of capsaicin, prodrugs and resultingcyclic urea can be reported.

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of the disclosure and scope of theappended claims.

What is claimed is:
 1. A compound, or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate, or hydrate thereof, that is:

wherein: R₄ is each independently hydrogen or substituted orunsubstituted alkyl; wherein a substituted group is substituted with oneor more groups independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, fluoroalkoxy, and amino; wherein the compound isnot (E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl2-((methylamino)methyl)piperidine-1-carboxylate, or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or hydratethereof.
 2. The compound of claim 1, wherein R₄ is substituted alkyl. 3.The compound of claim 1, wherein R₄ is unsubstituted alkyl.
 4. Thecompound of claim 1, wherein R₄ is hydrogen.
 5. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, or hydratethereof, and a pharmaceutically acceptable diluent, excipient or binder.6. A method of treating pain in a subject comprising administering tothe subject a therapeutically effective amount of a compound of claim 1,or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or hydrate thereof.